Presentation by Dr Nikolai Sepetov, CEO and Chief Scientific Officer of Nanosyn, for Grand Rounds In Mayo Clinic. Nikolai has described drug discovery opportunities for small players in the biotech world. With the microfludics screening technology explained this presentation will be very useful strating point for anyone, who is planning preclinical drug discovery studies.

1. Chemistry to Clinic: The Nanosyn Approach to Bridging the
Gaps in Translational Research
Dr. Nikolai Sepetov, Chief Scientific Officer and CEO
Mayo Clinic Center for Clinical and Translational Science
Grand Rounds, January 16th, 2015

2. DISCLOSURES
2
Mayo Clinic College of Medicine is accredited by the Accreditation Council for Continuing
Medical Education to provide continuing medical education for physicians.
Mayo Clinic College of Medicine designates this live activity for a maximum of 1.0 AMA
PRA Category 1 Credits™. Physicians should claim only the credit commensurate with
the extent of their participation in the activity.
 Planning Committee Members Commercial Interest/Off-Label Use:
No disclosures: Laurel Carlson, Michael Crowell, PhD, Katrin Frimannsdottir,
PhD, Colette Gallagher, Tauna Juenger, Glenn Smith, PhD, David Warner,
MD, Karen Weavers, Scott Kaese, Anthony Windebank, MD
 Speakers Commercial Interest/Off-Label Use:
No disclosures

3. LEARNING OBJECTIVES
3
Upon completion of this activity, participants should be able to:
• Describe drug discovery opportunities in small biotech companies and academia
• Describe advantages of breaking down the entire pre-clinical drug development
process in small manageable units with “go/no go” decision points
• Explain the use of microfluidics screening technology in drug discovery
• Describe novel models of collaboration between academic groups and industry

4. The Discovery to Market Path
4
http://innovation.org (PhRMA)

5. Industry Trends
Shifting gears in Drug Discovery and Development
 Away from “Fully Integrated Companies” to “Network Based Businesses”
 Large Pharma moving away from early drug discovery; RD restructuring
 Virtual companies and biotech firms are more involved in the initial phases of
drug development
 Increasing role of Academic institutions and Foundations as source of
innovation
 Growing role of CROs - partners relationships; industry concepts implemented
in academic research
5

6. The “Lean Thinking” Approach
6
“The lean producer, by contrast, combines the
advantages of craft and mass production, while
avoiding the high cost of the former and the rigidity
of the later…”
(The Machine That Changed the World : The Story of Lean Production, by
Womack, James P., Daniel T. Jones, and Daniel Roos, New York: Rawson
and Associates; 1990., p.13)

7. NANOSYN -Drug Discovery Contract Research Leader
Established and growing CRO partner providing drug discovery and
development services on demand
 Serving biotech and pharma community for 17
years (since 1998)
 Two research sites in US (San Francisco area):
• Santa Clara chemistry and biology discovery services
• Santa Rosa, CA FDA inspected kilo lab facility; cGMP
 Proven track record of advancing small
molecules from initial hits to IND
 Cutting edge technology and operations
 70 scientists (>50% Ph.D.)
 Completely US based
 No competing drug discovery efforts
 All IP belongs to Clients
7

8. NANOSYN Evolution
8
1998-2004
•Company
started; Focus
on micro-
chemistry
technologies
•Chemistry
services;
contracts with
multiple biotech
2008
• Acquisition of
assets of
Amphora
Discovery
• Biology and
integrated drug
discovery
services
offerings
2009
• Acquisition of
cGMP kilo lab
• Process
chemistry and
cGMP services
2011
• Moved to a new
state-of-the-art
facility;
• 40,000 square
feet; chemistry,
biology and
integrated
discovery
operations
2014
• Focus on
integrated drug
discovery
services;
• Multiple
milestones
reached in
collaborations
with academia,
foundations and
biotech
companies

9. Examples of In-House Technologies to Support Early Drug Discovery
Innovative Pharmaceutical Solutions for Discovery
Chemistry, Biology and cGMP Manufacturing

10. 10
Microfluidics Technology: via Acquisition of Amphora Discovery
Founded in 2001
Spin-off of Caliper Life sciences
~$100 million investment
State of the art microfluidics
platform
High quality microfluidic-
based enzymatic assays
High quality compound
library (made by Nanosyn)
100 HTS campaigns run vs.
~130,000 library
High quality hit & lead
programs
• In 2008 Nanosyn acquired all assets of Amphora including
IP and 26M data base of activities

11. Microfluidics Technology: Mobility Shift Assay
Enzyme
Labeled
substrate
384 well plates with compounds
P
S
S
Ac
K
K
Kinases or Phosphatases HATs or HDACs Peptidases
Sample in
a 384-well
Plate
V
DetectorProduct Substrate
_ +
Fluorescence
Sample1 Sample 2 Sample 3 Sample 4 Sample 5
(inhibitor)
Product
Substrate
11

12. 12
Advantages of Microfluidic Based Screening Approach
 Precision: Ratiometric, simultaneous measurement of substrate and product drives higher
precision
 Robustness: No constrains on structure of peptide substrates; Minimal interference from
fluorescent compounds
 Applied to multiple targets: Library of 300+ peptides representing natural protein substrates
is available; Successfully used with different classes of enzymes
 HTS enabled : 100,000s samples a day
 Ability to do multiple measurements in real time
100 200 300 400 500 600 700
Fluorescence
Time (seconds)
Detection of product and substrate in real time
SubstrateProduct

13. › Currently 6 Caliper
instruments in operation;
additional instruments are
available as a back up
› Proprietary library of
peptide substrates
› 2 Caliper Sciclones
› 3 Biomek FX robotic
systems
› 1 Bulk liquid dispenser
› 6 (Six) 384-well Multidrops;
including nL capability
› 2 Molecular Devices
Flex Stations
› 2 Molecular Devices
Spectramax Plus
› Barcoded sample tracking
› Analyst HT
› 2 Molecular Devices
Spectramax Plus
Equipment and instrumentation to support HTS programs
13
Largest Collection of networked, climate controlled microfluidic HTS
instruments in the industry

14. 14
Nanosyn Kinase Panel
Group Assays #
TK 100
AGC 36
CAMK 42
CMGC 33
OTHER 18
STE 15
CK1 5
TKL 7
Lipid 7
Atypical 2
Kinases
• 300+ non redundant kinase assays is available
• New assays are constantly added
• Flexible profiling formats: single concentration and IC50
• Flexible compound submission requirements
• Mechanism of action studies

15. 15
Nanosyn epigenetic assays
KDMs
HMTs
HDACs/SIRTs
HATs

16. Fragment Drug Discovery Technology: Ligand Efficiency
16
Integration of fragment screening and library design
Gregg Siegal et al. Drug Discovery Today V12, N23/24, 2007
LE =
-RT(IogIC50)
N

17. Microfluidics Technology - Reliable Detection of Weak Interactions
17
100 mM
-10
0
10
20
30
40
50
60
70
80
90
100
10%
IC50 Estimation
Inhibition,%
IC50
Log Compound concentration
900 mM
Affords measurement of weak
interactions
Robust:
• No limits on compound concentration
• No limits on cofactor concentrations
• No interference from fluorescent
compounds
Microfluidics Technology Supports Demanding Requirements of Fragment
Screening

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The Power of Two-Dimensional Screen
Rock2
200fragmentsactiveinROK2assayrankedbypotency
42 13 19 16 9 19 18 3 7 21 22 -6 14 30 13 15 21 31 24 3 -3 36 1 18 4 7 9 14 22 3 6 6
70 53 55 22 9 34 31 17 6 29 35 5 33 44 41 19 16 20 46 2 6 59 -2 47 6 6 20 12 16 10 17 23
46 28 30 5 9 13 11 -3 5 9 12 4 18 23 39 19 18 32 16 -27 3 30 6 8 20 10 3 5 6 8 11 15
32 19 19 1 9 8 6 6 2 6 7 2 15 14 22 14 15 13 11 -22 0 17 3 -1 5 7 -1 3 3 5 6 3
25 7 13 8 8 10 12 -1 2 12 13 0 9 11 7 15 11 22 12 5 1 17 0 3 5 3 4 8 12 1 3 11
58 24 35 23 13 35 29 12 4 35 34 -2 11 18 1 10 8 36 36 -10 -3 61 -3 16 9 9 8 18 43 2 6 -1
82 62 63 38 37 36 43 39 16 48 50 13 36 45 36 32 33 38 80 22 15 78 10 52 22 20 33 23 38 15 23 38
41 12 23 15 9 23 18 6 0 22 21 -4 6 13 11 4 5 25 19 -7 -3 29 -3 -3 1 3 1 19 22 -3 3 -8
57 37 38 12 7 26 19 11 3 20 21 5 24 36 28 13 16 9 29 -1 5 54 -1 37 9 12 12 8 7 8 10 10
36 1 10 9 6 7 10 14 22 9 11 4 62 23 21 60 7 10 37 44 2 24 5 11 17 17 38 4 5 -4 11 36
86 89 88 42 26 0 81 79 88 85 87 64 90 72 125 87 76 79 85 82 44 68 57 62 73 77 90 54 80 65 86 62
63 28 37 16 23 8 39 16 18 38 41 -1 37 21 17 34 -1 11 71 -52 3 32 3 6 14 11 18 8 8 8 12 -31
48 13 24 22 14 18 25 27 32 26 29 27 59 32 49 31 76 81 65 51 2 73 61 59 31 28 36 16 29 38 49 49
74 44 48 27 22 22 31 21 10 32 35 1 23 43 39 18 10 27 53 6 9 45 5 16 12 8 18 11 15 5 11 18
18 8 25 8 7 5 7 3 4 6 8 13 5 3 6 10 2 3 0 -2 6 13 2 5 4 2 5 3 6 1 0 13
87 82 89 38 27 -2 81 75 88 87 89 88 88 50 101 84 70 79 81 77 38 61 54 64 67 63 89 46 68 59 85 71
23 21 24 12 5 13 13 5 1 13 15 4 9 13 8 8 1 1 9 -6 -1 29 -1 12 -1 3 8 9 13 0 7 -28
46 39 43 24 12 11 24 3 2 26 27 6 20 20 20 17 -1 6 22 -5 5 35 -1 16 4 8 4 6 11 5 3 4
9 9 7 8 12 4 7 4 3 5 6 6 18 0 20 19 17 18 10 16 7 20 4 7 2 4 6 6 4 2 6 13
27 -3 6 9 9 5 8 12 15 7 7 7 57 18 36 54 3 5 18 31 4 20 -6 8 13 12 28 3 3 3 8 19
85 59 85 24 22 5 51 63 74 40 50 40 73 27 37 57 48 41 71 78 -9 58 58 38 32 22 84 22 55 5 36 28
41 32 52 9 9 7 12 71 80 13 13 54 97 59 75 66 50 29 59 70 77 75 42 67 32 23 94 57 50 88 103 77
4 9 2 5 3 6 4 -5 -3 5 5 -10 2 3 4 0 -6 -5 -1 -12 -6 27 -7 2 -4 -3 -3 -3 2 -5 1 1
32 48 10 4 5 14 4 7 10 4 7 15 17 18 16 12 18 7 59 -36 3 46 -1 10 14 11 12 15 20 3 4 -2
33 10 14 14 9 11 18 21 23 19 21 14 42 23 41 23 70 68 49 48 4 61 48 46 30 19 22 10 18 30 37 34
26 50 13 8 9 17 9 -3 4 9 9 -4 17 15 13 18 9 10 40 -37 3 43 -1 6 12 9 8 10 18 0 6 -21
49 18 27 12 21 8 28 8 10 26 28 11 31 3 16 26 0 9 59 -57 3 23 2 6 10 9 11 6 6 3 7 -13
56 13 47 11 4 12 10 7 6 12 12 -3 21 13 9 23 15 14 40 -46 2 27 13 6 10 8 11 11 6 3 17 -43
10 3 16 7 8 4 6 -1 3 5 5 2 4 10 21 4 1 -56 3 -1 7 7 3 6 6 2 1 2 2 1 1 6
7 3 7 8 9 10 5 5 2 10 9 -1 13 3 14 5 0 4 8 1 -1 13 7 25 1 2 -2 0 5 20 12 8
26 24 26 10 -3 6 10 10 2 9 13 -3 7 12 8 3 7 6 27 2 3 29 3 9 14 5 4 3 3 3 1 -7
15 10 32 11 12 11 10 -8 1 7 10 0 6 9 14 7 -2 10 15 -8 6 10 6 5 -1 2 5 1 2 0 2 -2
15 41 17 8 11 7 7 7 2 5 8 3 7 11 13 7 2 7 14 -1 2 33 3 13 5 2 5 6 8 2 4 11
35 11 14 14 8 10 15 29 28 11 14 38 60 23 18 61 15 9 17 37 5 35 6 16 24 20 43 15 32 -2 15 11
29 11 14 5 7 7 8 7 2 9 9 4 7 12 11 8 10 5 24 -1 2 14 4 3 8 5 4 2 3 3 4 11
30 14 13 9 7 8 11 7 3 10 10 -4 17 20 31 11 19 3 26 -2 7 41 5 28 7 5 5 16 15 1 5 -6
13 7 3 8 9 4 7 -2 3 9 8 3 4 4 8 7 3 -3 17 1 3 17 2 8 3 2 5 6 5 0 4 13
15 16 16 11 9 10 10 5 1 10 11 0 6 7 9 5 2 0 7 -3 3 5 1 3 0 1 3 9 6 3 5 -3
31 23 25 16 11 9 17 2 2 18 18 0 10 14 17 9 4 4 25 -7 2 10 -1 3 5 3 0 6 5 4 2 -18
59 81 43 -4 -14 -5 2 8 1 1 1 -6 33 38 17 32 7 22 29 18 4 44 12 14 6 9 3 0 4 10 6 13
20 27 7 1 1 7 3 3 5 3 3 5 9 20 9 7 16 3 43 -43 1 24 1 7 9 4 7 8 12 3 2 -11
27 8 37 5 6 5 8 63 62 8 8 38 94 32 55 53 36 13 55 56 70 61 28 56 20 16 81 41 34 80 99 59
6 -3 8 5 2 6 5 0 -5 5 4 -8 -4 -5 -14 0 -4 -3 6 -5 -7 4 -6 -6 -8 -5 1 -2 -4 -3 4 -11
19 35 7 6 12 17 9 -5 3 8 9 6 10 7 16 9 1 4 27 -50 1 28 0 3 6 4 5 7 18 -1 5 -21
42 62 33 1 0 1 21 17 13 18 18 6 38 24 14 34 14 15 55 -21 -4 42 1 26 13 7 19 3 8 8 6 7
48 31 28 19 12 22 36 7 3 29 35 23 15 30 17 14 21 16 31 -32 2 45 2 29 2 3 6 11 12 5 7 -12
1 -9 4 4 3 2 4 -2 -4 3 4 -4 -1 -1 -3 -2 -3 -5 -1 -8 -5 8 -6 -7 -5 -3 -4 -1 -3 -7 -4 -9
71 33 28 19 12 8 19 61 13 20 20 0 33 28 23 6 42 14 48 14 2 31 14 20 11 8 16 4 10 15 33 15
11 14 6 8 8 6 8 0 1 7 8 4 6 3 8 6 -3 3 14 -4 3 19 -4 5 1 3 2 8 10 0 3 4
3 0 5 4 7 10 6 4 4 8 9 4 18 7 18 5 -6 -1 7 11 -2 17 9 25 4 4 1 -3 6 18 18 -13
16 27 14 5 7 4 7 6 2 7 7 -6 15 9 26 5 9 4 37 1 2 34 8 5 6 7 4 14 17 1 3 -11
19 23 45 0 -5 3 4 4 -2 4 6 8 10 8 6 11 7 -1 10 10 -1 32 -7 1 6 1 0 -2 1 -2 -2 7
77 58 76 6 4 1 34 74 86 31 40 73 91 78 90 73 81 50 80 81 67 75 62 65 68 61 93 49 60 54 94 72
56 28 82 19 18 17 21 11 7 21 23 18 18 28 25 18 14 34 18 7 6 36 6 17 16 14 17 11 15 11 6 20
10 15 17 4 1 3 3 0 0 1 3 15 5 6 7 3 10 3 11 -5 10 18 1 7 7 1 2 4 0 2 1 -9
53 40 25 31 -7 41 33 16 4 37 39 -8 9 19 16 13 41 61 22 9 -1 35 17 7 14 11 9 4 12 3 3 18
70 63 80 8 -10 21 24 32 12 24 25 -9 49 51 22 38 25 51 39 6 7 69 10 38 14 10 21 23 40 11 10 18
39 5 26 6 6 6 7 8 5 6 7 3 15 11 7 11 6 4 15 -46 0 24 10 1 6 4 6 6 5 0 8 -52
82 47 72 -1 2 2 0 29 57 -1 -3 30 62 26 56 57 23 23 71 61 -3 48 5 21 32 30 78 5 25 -9 16 57
10 24 11 4 10 6 6 1 3 4 5 2 8 6 12 6 2 5 7 -1 3 15 6 4 4 2 3 5 3 1 3 6
21 -3 8 9 18 8 10 17 17 8 8 36 38 16 19 31 6 9 7 30 4 30 4 7 18 11 18 10 22 3 12 26
33 11 14 10 10 7 11 1 10 13 13 8 19 18 17 18 7 3 70 8 3 33 -3 15 8 7 8 8 9 9 9 18
18 -8 9 4 4 4 7 0 0 5 6 -2 6 5 8 4 6 0 15 0 5 6 2 -4 2 2 0 1 2 1 4 10
44 72 41 -2 -4 0 21 24 31 19 17 32 64 34 45 63 25 22 43 18 1 54 5 43 14 11 36 9 14 10 11 16
5 3 49 8 10 0 7 0 1 6 8 8 3 10 20 5 13 5 5 6 1 9 1 2 3 3 3 5 9 3 2
84 85 83 12 8 0 42 59 86 31 40 34 72 38 34 61 68 62 72 71 5 51 34 46 51 48 78 23 23 30 50 53
17 19 14 4 -8 2 2 -5 1 3 5 -1 5 7 16 2 3 2 18 5 8 21 -1 4 14 2 0 1 7 4 1 3
18 8 7 8 5 5 7 -1 3 7 6 2 11 11 9 9 7 5 22 -1 2 23 4 6 -1 3 2 12 10 4 2 -17
55 9 58 8 9 13 9 22 55 9 9 17 61 25 35 62 13 11 48 53 2 36 9 24 21 18 57 6 15 -5 20 45
11 13 18 9 14 10 9 -5 1 8 8 5 5 0 15 7 -1 7 10 -9 5 9 3 0 1 0 3 6 1 -2 7 -4
10 3 2 8 8 4 6 5 3 7 7 8 2 2 8 5 1 3 22 1 4 9 -1 1 1 2 2 4 4 3 1 3
8 19 12 8 15 4 15 2 3 13 18 4 5 12 11 8 9 4 69 9 -3 44 -3 5 5 7 5 15 19 5 3 14
11 6 9 2 8 6 1 0 7 4 3 -4 2 7 25 1 15 6 5 0 2 18 -1 8 3 3 1 4 5 5 5 12
29 13 15 12 11 11 13 2 9 11 15 20 17 20 19 20 11 2 72 6 2 38 1 11 9 7 8 6 9 4 4 8
24 3 12 9 7 4 9 24 5 9 10 10 16 11 16 10 78 36 20 5 2 42 8 11 20 11 9 23 40 4 14 15
4 -1 1 1 0 0 1 4 1 0 0 -12 8 -1 -2 1 3 4 2 0 1 13 2 -1 3 1 3 0 -4 -1 -1 -24
26 61 31 13 6 15 12 13 4 12 16 10 9 10 18 12 10 -1 13 7 8 27 -7 10 7 9 8 15 5 5 12 7
12 10 5 7 13 3 14 10 9 12 14 3 5 9 5 6 6 5 68 4 2 43 -6 7 7 12 5 14 15 6 4 11
24 54 20 -3 -2 -2 10 14 6 9 8 3 31 20 3 25 7 11 38 -42 -1 32 -8 19 10 3 10 2 2 6 5 0
44 71 28 -5 -18 -6 -3 7 0 -3 -2 -2 19 29 39 22 3 9 14 10 3 37 6 -4 0 2 0 -2 0 1 1 7
7 -3 4 2 6 3 4 -1 -4 2 3 -4 -4 -7 -5 -3 -11 -6 -1 -10 -2 -4 -6 -8 -6 -4 -1 0 -1 -4 4
11 21 10 6 4 4 5 49 29 5 5 31 62 24 35 57 60 59 49 58 -1 51 60 49 27 25 58 16 8 11 25 55
59 28 20 13 10 6 13 46 4 15 14 3 23 17 15 7 28 6 36 8 5 14 6 16 2 5 4 3 4 15 20 9
41 9 50 9 -2 8 14 17 23 13 11 -3 61 25 21 59 12 11 21 44 -2 36 2 11 26 16 47 0 6 -4 14 44
33 21 19 15 10 13 23 5 2 21 24 8 9 18 21 9 15 8 18 -22 7 26 -2 22 -1 2 6 5 13 8 6 -2
12 17 6 3 -2 3 2 -3 -5 3 2 -12 4 7 -2 1 -9 -7 3 -7 -4 4 -7 -2 -2 -3 -3 -2 -2 -6 -4 -17
25 49 55 1 -8 -2 10 5 5 10 9 -2 45 33 34 48 15 18 33 -25 0 52 -3 45 10 4 11 7 9 12 4 0
2 4 5 7 5 6 5 2 4 4 11 15 0 15 14 5 2 35 -3 7 8 -1 2 4 2 5 5 3 2 4 -43
4 -1 -1 0 1 0 -1 6 1 -3 1 8 6 5 5 6 12 1 24 6 2 13 -1 2 4 2 6 3 4 1 2 4
26 63 26 -4 -3 1 8 9 15 10 8 18 48 30 35 46 14 12 24 -19 0 48 -2 39 11 6 17 6 11 5 5 0
12 -24 8 5 7 3 3 3 2 5 4 3 8 5 4 9 3 5 29 1 4 28 5 -1 7 4 1 6 11 2 3 -16
4 2 5 8 10 7 8 1 0 7 8 0 4 3 6 3 1 -2 6 -4 1 1 -2 1 2 2 -1 3 4 0 2 -2
11 8 30 -2 -5 -3 0 -3 -3 -1 2 -2 3 10 -2 3 7 -3 7 3 -1 18 -6 2 -2 0 -3 0 -2 0 -1 -4
57 44 72 4 -17 7 11 18 5 11 13 -2 35 47 39 27 12 44 24 -4 -2 55 6 8 3 3 11 20 19 6 3 10
7 6 9 -2 -1 0 1 0 3 0 1 4 3 12 -1 2 13 5 6 1 -2 11 -2 4 0 -1 1 4 1 5 1 -9
30 21 52 12 13 9 12 11 11 12 13 0 35 16 28 32 -2 -1 27 16 1 43 0 -2 7 8 20 7 11 0 9 15
9 -4 9 8 7 4 8 -6 1 5 6 13 2 -3 6 6 6 -2 13 -1 3 24 0 9 6 3 4 9 8 1 2 10
6 8 3 3 5 2 4 9 3 4 5 -5 25 10 16 26 8 0 34 -14 0 7 -1 -1 5 5 10 6 6 -2 6 -18
40 6 15 18 -7 25 19 13 3 19 21 0 7 15 10 4 17 48 16 5 1 19 9 5 9 4 6 5 8 7 -1 11
9 8 -4 0 3 1 -2 3 -1 -3 -3 9 7 2 7 7 1 3 6 1 0 2 4 1 3 -2 7 0 -1 1 12 13
41 18 71 14 10 9 16 8 5 14 16 2 14 28 23 11 5 25 9 -1 7 14 0 5 8 8 10 7 8 6 1 5
11 -10 8 5 7 5 4 4 2 5 6 1 7 -5 4 9 3 2 6 5 2 8 2 2 1 4 5 7 4 -1 5 -4
2 0 2 4 6 5 3 0 -1 4 4 9 3 -9 -3 5 2 -2 2 -2 5 4 -1 0 3 2 2 5 5 -1 2 -12
8 20 8 5 6 5 3 -4 -1 3 4 -5 -1 0 -5 3 -4 17 2 -11 -8 12 -5 -3 -3 -1 2 0 1 -7 -1 -10
2 -8 5 6 7 4 5 0 2 4 5 3 14 7 14 10 10 -3 7 12 3 13 3 7 0 1 3 5 2 1 1 12
8 7 23 4 5 4 6 16 25 6 6 9 46 18 36 19 46 36 42 56 6 56 35 48 14 15 30 0 25 28 36 56
9 4 7 1 5 7 2 1 -1 4 4 1 8 5 2 3 4 4 4 -4 -1 8 1 6 4 4 -6 4 3 7 6 5
75 44 62 -1 6 1 -1 30 51 -1 -2 34 58 27 41 54 20 15 63 52 -3 52 6 24 25 26 67 4 22 -11 13 43
15 -1 9 5 6 2 7 -7 2 6 6 2 6 6 11 7 74 21 11 3 6 26 8 3 8 6 -1 15 25 14 6 1
3 -2 34 6 7 0 6 0 1 5 6 0 5 0 -1 5 0 1 4 -1 1 0 0 -4 1 2 2 -3 3 2 3 6
61 33 73 9 7 18 10 7 3 12 14 1 17 13 22 16 6 26 20 12 0 44 3 16 6 4 59 8 9 1 7 17
51 48 68 13 17 6 24 51 72 19 21 26 68 31 61 52 22 19 52 74 -1 36 59 12 26 18 79 7 20 -5 26 48
7 5 6 0 -6 1 -5 2 1 -2 0 -1 4 4 4 2 3 -5 4 5 2 5 -3 4 2 0 2 -96 0 -4 -1 10
14 -19 7 2 3 0 1 0 13 -2 -2 -4 57 9 8 56 9 4 5 35 -3 20 13 8 16 11 35 0 3 -7 6 23
53 31 39 11 11 1 20 25 51 17 16 28 59 27 60 57 26 20 70 65 -3 55 4 34 29 25 65 6 34 -8 18 60
34 10 40 -11 -20 -11 -3 9 8 -4 -8 1 59 20 11 52 9 8 34 8 -1 66 -4 44 5 6 48 17 18 -2 21 31
32 12 28 8 9 4 8 4 3 7 7 -2 11 15 17 15 10 13 22 5 7 40 -1 11 11 7 3 16 40 2 4 14
38 0 45 6 13 10 7 10 40 6 7 14 62 8 37 63 7 6 28 40 2 33 7 16 23 17 47 7 6 -6 14 37
6 8 7 6 5 4 2 45 23 3 2 12 58 26 43 58 28 38 39 54 1 44 57 19 21 22 52 6 7 -5 19 53
19 10 7 6 10 10 7 7 6 10 9 -1 12 13 11 3 15 7 41 19 1 84 5 18 3 6 2 6 21 21 11 -10
22 14 57 9 6 6 16 6 6 16 19 -3 6 6 7 15 8 9 25 -2 -1 38 0 8 4 2 5 5 3 2 9 2
9 7 11 6 14 8 8 4 3 4 7 17 6 9 14 11 8 5 17 4 4 23 3 9 4 1 6 8 7 4 0 -13
18 46 20 9 7 8 9 7 3 9 11 0 5 16 22 7 2 -2 9 3 2 2 -3 2 5 4 4 6 3 2 6 2
1 -1 1 -1 0 0 1 1 0 -1 -1 0 -1 1 -2 -3 1 2 6 1 0 6 2 2 3 0 1 1 0 2 -2 -2
27 1 31 -1 -1 5 6 4 13 4 4 -2 43 17 18 34 4 6 6 29 -5 27 -4 0 8 9 24 3 0 0 7 35
15 33 42 -2 -3 -3 4 4 2 4 4 1 27 30 24 29 10 7 17 -26 -5 37 0 46 5 1 5 5 8 9 0 1
3 15 6 6 7 6 5 1 2 5 6 1 13 3 10 9 1 1 6 5 1 -7 2 1 -2 0 4 4 0 1 2 10
28 35 22 18 8 12 18 4 -1 18 20 -2 10 22 28 13 0 5 14 1 1 11 6 0 6 5 2 2 3 8 10 13
4 6 7 3 2 1 1 -3 1 2 2 2 4 -6 -14 4 3 4 2 -62 0 3 4 -2 3 1 2 4 1 -2 0 -44
38 28 42 31 5 7 30 16 14 30 32 2 15 23 30 8 16 9 35 18 2 45 9 14 15 10 6 3 9 15 10 22
54 17 75 22 17 40 23 7 24 25 6 13 13 19 18 19 16 39 9 8 56 3 32 19 17 27 23 29 5 8 1
14 12 10 1 5 0 0 4 1 1 3 8 9 10 19 8 3 6 22 6 1 9 5 -1 4 3 13 2 2 4 11 13
6 1 3 4 7 3 4 -1 1 3 4 -8 2 1 2 2 1 -1 2 -4 -5 3 -3 -1 -3 1 3 0 4 2 3 1
4 -3 6 0 -1 0 0 2 0 0 -2 -1 2 3 2 1 6 4 3 4 2 5 3 6 2 1 4 0 1 3 3 20
7 17 12 6 5 7 7 1 3 9 8 3 4 6 4 -1 53 9 14 2 1 18 2 12 0 0 0 17 20 2 9 17
56 39 72 25 9 2 43 56 63 32 38 61 82 35 48 59 62 48 74 59 49 79 52 71 35 34 86 49 50 60 85 55
35 9 33 -5 -6 -3 -2 10 6 -5 -4 7 25 10 10 22 2 2 2 31 2 15 12 0 10 10 -3 0 -1 2 21
50 21 64 9 5 16 12 7 4 12 14 7 27 2 14 29 14 21 27 16 5 54 4 39 13 6 51 11 8 2 7 9
7 6 2 0 2 1 1 -2 -4 0 1 -5 0 -7 3 -2 -12 0 -4 -15 -1 -1 -8 -4 -3 -3 -3 -4 -2 -2 0 -2
38 22 66 29 1 6 32 8 4 34 35 -9 6 13 6 8 5 4 23 9 3 44 -4 21 6 3 11 12 24 5 3 24
4 -14 4 -1 0 1 -1 4 0 -3 -2 3 7 3 5 4 6 2 0 3 9 1 4 11 0 -2 0 -3 0 2 4 -5
1 6 2 -7 -9 -3 -5 4 3 -6 -5 -5 15 3 4 11 5 -1 5 13 -3 3 1 0 7 1 4 -1 -1 0 10 4
59 46 65 4 2 0 16 62 78 15 19 63 91 64 85 68 77 40 76 76 60 70 57 58 47 46 90 44 55 50 92 64
77 41 89 23 36 36 29 38 50 27 31 5 30 41 29 32 28 49 82 -38 10 78 -2 65 47 41 60 29 69 4 27 64
4 3 4 4 8 6 6 -3 2 6 6 6 3 8 12 6 2 -2 2 -4 1 8 1 4 -1 2 3 4 4 0 4 -5
3 -1 1 0 0 -2 0 4 1 -1 -1 2 3 8 8 3 10 0 17 6 5 7 -1 5 -2 1 2 2 1 4 3 4
15 -6 5 6 1 0 8 8 5 6 9 3 43 10 12 30 14 0 8 -1 -6 27 -2 3 3 5 11 8 9 -4 9 9
31 13 53 12 7 15 11 5 3 11 13 11 6 17 14 13 13 8 19 -3 4 48 -1 15 6 11 8 13 18 4 3 -7
50 3 14 -2 4 3 5 6 8 4 2 4 61 13 19 59 19 9 51 -9 2 65 0 16 33 23 45 10 10 5 11 27
5 9 6 5 9 7 5 4 -2 5 4 0 3 3 7 5 0 -4 5 2 1 3 3 1 2 5 2 2 1 -1 2 2
-24 32 10 4 4 2 2 3 -2 4 3 -11 14 12 13 6 9 3 11 4 0 11 6 9 4 2 6 1 2 -1 3 -3
18 7 38 7 11 9 8 -2 2 8 9 10 20 2 21 17 -1 6 12 6 1 38 2 0 5 6 9 5 9 4 5 7
68 9 38 15 6 16 13 0 2 15 14 5 21 9 5 21 6 10 6 7 1 15 6 4 1 3 10 5 6 2 8 12
6 2 15 1 2 5 4 11 12 4 5 10 37 22 31 13 31 21 32 47 7 43 34 40 10 9 28 1 18 23 35 46
5 -2 5 7 8 3 7 1 2 6 6 -1 -2 4 12 2 2 1 3 2 4 1 -1 1 -3 2 1 4 4 0 1 4
8 9 14 3 2 4 0 9 7 3 2 4 29 24 32 9 42 16 18 -33 3 25 21 31 5 4 2 4 7 23 27 0
29 9 27 0 -9 0 2 4 1 2 4 -5 3 3 -1 3 4 2 2 -1 -2 8 1 0 2 1 4 5 5 0 2 7
1 2 3 7 7 8 4 -1 -2 5 4 0 1 0 3 2 0 -2 6 -1 3 -1 0 3 0 0 0 7 3 3 2 -1
37 5 27 9 12 9 8 8 7 10 11 -1 3 8 9 1 21 14 9 -29 2 16 6 17 9 9 4 4 6 14 22 4
3 15 5 8 6 4 7 7 1 6 9 -39 17 4 9 17 -8 5 16 11 -1 39 -5 9 3 5 6 18 19 -3 3 6
65 74 73 6 4 -1 17 42 77 14 15 42 71 29 60 59 44 59 61 70 0 48 37 24 41 39 72 9 6 -3 43 51
16 11 37 8 11 6 7 4 1 3 7 22 4 10 11 5 14 4 -3 -1 4 19 7 10 10 5 3 7 6 6 2 8
4 5 5 0 4 2 3 -1 5 1 1 7 7 3 10 11 16 8 9 14 2 15 12 9 8 3 11 1 5 7 13 17
7 11 10 4 4 2 3 -3 1 5 5 -1 9 10 12 3 10 3 7 4 1 8 6 10 5 0 6 1 6 3 10 17
3 15 4 4 5 3 3 -5 -2 4 4 -4 7 -3 -6 3 -1 16 5 -8 -2 10 -3 -9 -6 -3 -3 1 -1 -3 0 -13
2 7 8 5 4 9 7 11 9 5 6 -3 61 17 20 61 10 6 13 30 3 12 2 1 17 12 49 6 7 1 13 28
50 37 56 13 9 -1 26 55 80 18 22 45 94 62 85 78 60 48 50 84 42 87 53 76 22 19 83 35 41 55 91 80
2 1 4 2 2 4 2 2 2 4 2 -1 -3 1 7 -5 14 10 -2 2 2 6 6 7 1 0 1 0 3 1 5 19
20 23 12 3 3 12 5 3 0 4 4 5 9 9 -2 11 -4 27 10 -79 3 3 -2 2 1 -1 5 2 1 0 4 -2
11 44 12 5 -1 4 6 0 5 7 7 9 -1 18 0 -4 4 3 7 -121 -8 20 1 7 -10 -2 4 6 5 2 -1 -17
15 8 6 5 10 8 6 0 0 9 9 2 7 10 1 2 9 5 31 11 -1 73 6 17 5 5 -1 4 14 26 11 15
45 16 50 1 -8 9 10 20 15 11 12 -1 61 27 18 59 26 39 60 13 1 80 17 65 -10 9 67 37 72 9 15 42
4 5 4 8 11 5 6 2 2 3 7 16 2 1 7 2 6 5 -2 1 5 8 4 4 1 3 2 5 5 -2 3 4
6 25 2 -4 -10 -2 -5 7 1 -6 -3 -4 7 13 3 2 5 2 11 7 8 34 -2 5 2 2 2 -3 9 -1 -1 6
9 0 4 0 1 3 4 2 2 4 3 3 14 6 17 4 11 6 10 -3 -4 10 2 5 7 3 5 4 3 3 6 15
5 11 5 6 9 4 6 -2 1 3 5 8 5 9 12 8 7 -2 12 3 7 15 -1 8 5 2 5 5 6 6 3 8
40 12 13 7 12 14 9 13 19 8 10 -3 54 13 27 51 18 10 37 -9 1 54 3 11 24 21 28 10 15 -2 10 -15
4 -3 1 1 3 2 0 -2 2 1 1 2 -5 -2 -1 3 -4 -3 1 3 1 3 0 7 4 -1 1 1 1 0 -1 14
19 1 15 8 11 1 7 -1 17 6 7 19 56 12 26 53 12 3 6 49 1 26 43 6 -1 3 23 4 3 2 13 24
4 0 2 5 4 2 4 2 -1 5 4 5 -4 -2 1 -1 -4 -4 2 -6 2 3 -10 -11 2 1 -5 3 2 2 -2 5
20 23 57 6 6 7 7 3 2 6 8 8 13 4 12 15 7 11 5 11 9 28 2 11 3 3 9 11 5 4 6 16
21 6 20 5 5 7 4 -7 2 5 6 1 6 2 -2 7 7 8 16 1 1 27 10 18 -1 3 6 9 8 0 4 -6
60 20 79 26 15 48 32 22 14 31 33 7 13 22 15 14 17 36 71 -1 10 67 1 57 33 30 49 27 43 12 8 64
6 -1 1 2 0 -1 2 5 9 0 0 2 49 9 23 52 0 -1 11 29 -2 10 14 2 8 6 22 0 0 -8 3 17
10 30 9 3 7 3 4 0 1 4 2 2 8 9 11 10 -12 -5 13 -2 1 14 -2 -1 1 1 0 3 4 -1 -1 7
4 12 10 2 20 6 4 3 0 2 3 5 45 16 24 38 -2 7 12 5 5 13 0 3 5 2 17 3 3 2 17 6
5 -15 4 -1 -9 -2 -4 3 0 -3 -2 4 2 8 0 0 4 1 2 5 4 3 -3 5 0 3 1 3 -1 2 1 9
20 -4 19 5 8 8 4 0 2 6 5 0 8 8 13 6 11 8 11 0 3 25 -6 4 7 4 1 12 23 5 0 5
9 4 5 0 1 -1 1 2 2 -1 1 1 11 6 10 5 8 5 11 3 9 8 3 6 -2 0 8 -1 1 1 5 -10
23 21 32 18 4 4 19 13 7 17 19 3 14 13 19 4 2 2 24 12 1 29 8 6 9 5 1 -1 4 10 13 7
23 18 51 8 -7 -1 8 4 0 9 12 -8 2 7 2 4 4 0 6 5 1 15 -2 0 8 5 9 1 2 -1 4 8
5 15 6 3 4 3 5 3 0 6 7 0 4 -2 1 0 33 3 8 -2 1 10 4 11 4 2 -2 13 9 3 9 2
6 2 3 3 3 2 1 2 0 -2 0 2 2 -2 -2 3 -4 0 3 8 0 8 2 0 5 0 2 0 2 1 2 -1
17 22 16 11 6 8 13 2 3 14 15 1 5 16 21 9 -1 3 8 0 2 8 5 -2 -3 0 -2 2 4 3 3 4
56 -2 70 10 9 4 11 9 8 8 13 -2 65 21 29 64 24 55 17 37 8 25 20 9 15 19 63 7 10 3 23 35
68 -1 47 4 12 32 1 35 18 6 6 -2 52 66 69 20 85 66 77 -27 0 89 13 78 24 19 47 59 89 30 35 9
16 11 32 7 7 7 8 3 3 6 10 8 2 2 0 4 7 12 8 6 4 23 -1 6 1 4 9 6 5 3 4 -18
2 5 5 4 5 3 3 1 -1 2 3 1 3 -1 -5 1 2 4 4 -52 3 16 2 1 -1 1 0 3 2 3 1 -31
15 11 35 7 6 7 12 -2 5 11 12 3 4 6 9 3 0 5 9 -5 -1 24 -2 2 0 1 3 10 4 1 5 -4
27 6 7 -4 2 2 1 3 3 1 -1 0 56 10 20 51 14 9 33 8 -8 50 -6 14 12 10 29 5 9 2 8 16
26 5 18 -3 -10 -5 -3 2 3 -3 -4 4 21 8 12 15 1 1 -5 17 -9 16 10 1 5 2 5 -3 -1 -3 1 15
2 -4 4 -1 0 -1 -1 1 0 -2 -1 -3 2 0 -1 -4 0 -5 1 1 -2 1 -4 -3 0 0 -3 -5 -1 -1 5 -3
41 17 61 3 6 9 4 21 31 3 6 17 59 33 34 61 23 13 49 52 3 61 12 30 21 20 53 10 25 -5 11 44
9 11 8 0 4 1 1 25 29 -1 -5 16 47 17 41 14 29 16 55 50 39 41 -5 20 25 25 53 17 31 35 60 61
10 5 8 0 1 4 0 6 3 1 1 -8 6 2 7 7 4 -1 3 8 -1 12 2 2 1 3 3 3 4 -3 1 9
17 -3 26 -13 -9 -10 -4 9 7 -6 -7 -8 29 11 7 28 4 -1 19 4 -7 52 -7 32 6 -10 18 14 16 1 4 23
29 12 19 9 7 6 12 4 4 9 12 9 12 21 24 9 23 12 23 1 4 64 1 30 13 8 4 22 40 4 4 4
16 10 11 21 13 8 20 -1 8 17 20 12 9 14 15 11 4 7 36 -5 1 35 2 10 6 6 8 8 10 8 2 -1
10 9 35 -2 -6 -5 4 5 1 4 2 1 -2 6 -13 4 15 9 16 -81 -2 21 -2 9 1 3 9 1 4 6 8 -7
25 2 12 5 16 5 5 13 3 3 4 -4 1 3 4 8 -1 4 13 -3 1 13 -2 0 6 1 10 3 3 2 0 61
6 -4 8 3 5 6 2 1 1 4 3 -2 6 9 9 4 8 5 8 1 2 9 5 15 2 -1 1 2 3 5 0 -2
21 3 4 11 14 15 10 7 2 10 12 1 28 4 14 30 1 -3 5 8 2 13 0 4 -1 4 11 7 5 2 6 13
2 7 5 4 7 6 3 5 0 2 3 -36 5 5 13 6 -4 2 8 -1 2 4 -3 1 2 2 3 2 2 -3 5 -10
5 2 7 7 10 8 7 -2 1 8 7 -4 -1 1 4 -3 3 0 -1 -3 2 5 -2 4 5 1 -2 1 1 5 -9 2
12 16 33 4 5 2 3 5 3 2 4 7 7 8 10 5 3 7 11 6 1 25 5 13 1 2 6 9 6 3 4 5
9 43 20 1 15 3 3 31 42 2 3 -7 65 31 48 61 33 18 53 61 0 55 6 32 36 33 64 9 26 -6 30 52
2 0 3 -2 -4 -5 -1 -10 3 2 1 -6 -3 -3 -3 -6 5 3 0 2 0 5 0 3 -4 0 1 0 -1 1 3 21
5 11 7 -24 7 3 -18 7 3 -18 -21 5 0 6 2 1 -3 3 11 -4 -1 2 -1 0 4 1 4 4 0 0 0 13
5 8 3 7 14 5 7 4 1 6 6 0 11 1 1 6 3 4 7 -1 9 11 2 3 -5 3 0 6 5 3 2 3
65 34 88 14 30 22 18 21 32 19 21 17 17 21 36 19 12 30 70 -49 5 74 0 55 29 21 38 26 52 10 15 35
1 1 15 -3 -4 -3 1 26 33 -1 -4 9 58 16 39 55 23 18 59 59 -3 40 8 21 21 22 59 7 14 -5 13 56
4 3 3 -5 -8 -9 -2 -1 1 -2 -4 -5 1 2 2 2 -8 -2 11 1 -2 -3 1 -6 0 2 3 -2 -1 -5 -3 8
14 17 10 10 12 10 9 13 1 6 9 24 6 11 5 7 15 5 7 -1 9 33 6 16 5 3 3 9 8 5 3 5
3 4 0 -7 -12 -6 -6 4 1 -8 -7 -3 7 2 1 5 2 2 4 7 6 6 -2 3 -3 1 1 -1 -5 -3 2 14
3 5 7 6 8 4 5 -1 -1 7 5 -3 -3 5 3 -2 4 -2 -1 -2 0 2 -1 11 -2 1 -3 1 2 2 1 5
3 8 5 7 9 6 4 1 -1 9 6 -2 -2 1 -2 -2 -4 -6 0 -5 0 2 -5 -2 -2 0 -4 1 1 3 -1 -4
44 13 27 5 11 11 6 9 4 6 4 3 12 30 19 14 15 19 49 -92 4 66 -2 50 12 5 18 27 62 6 7 -8
53 9 24 11 10 12 10 -3 0 11 12 1 13 6 11 11 3 1 4 5 3 19 4 1 -3 2 4 12 10 5 4 -6
18 14 37 6 4 2 12 26 37 7 9 42 73 29 42 52 32 26 59 65 2 44 12 32 21 14 77 13 34 -3 66 48
12 6 12 6 5 4 8 9 0 3 3 -5 5 8 11 5 3 3 14 1 -2 17 -3 0 0 2 4 7 4 -2 4 9
51 6 62 9 14 4 10 8 6 10 12 10 64 10 35 64 12 47 12 35 4 30 3 5 20 14 56 7 8 -4 19 27
Kinases
5 1 2 3 5 2 1 11 1 7 -1 9 17
-4 8 2 2 5 9 14 6 6 1 2 2 5
-8 7 4 0 6 1 3 3 -1 2 7 -3 4
-8 7 1 2 1 3 4 0 1 0 2 0 3
4 5 -1 4 2 0 -4 8 1 10 1 4 8
-9 -1 0 -2 -1 0 -2 -4 -2 -3 -5 -6 0
22 14 6 1 12 14 8 7 11 3 8 11 10
-5 -3 0 -1 -2 -1 -5 -5 -4 -1 -3 -9 -4
-8 -1 0 -1 0 7 5 6 4 4 1 2 3
8 1 2 0 2 4 9 3 3 1 1 52 1
38 75 8 14 87 81 86 86 88 66 67 70 9
22 -16 -59 3 50 15 23 39 6 16 24 38 21
-4 7 -1 3 6 5 3 5 3 5 4 -10 1
18 9 6 2 10 9 5 5 7 4 11 7 5
-3 -4 3 1 3 5 7 3 0 -2 1 3 5
24 56 -37 -3 85 66 85 75 82 46 60 59 3
10 4 4 1 0 2 -2 2 0 0 1 -2 1
-5 2 -1 -2 5 2 1 3 4 0 -2 -2 0
-3 0 4 4 5 4 -1 4 1 1 4 -2 9
7 3 -1 12 2 4 3 2 3 1 2 2 8
28 47 -15 29 93 56 89 85 57 68 66 88 17
23 0 -5 -12 15 12 6 17 4 -19 3 -2 2
-5 2 -3 1 -4 -1 -4 -1 -3 -4 -5 -5 -1
3 -20 -23 8 45 9 7 28 4 7 3 31 6
0 4 -2 4 4 4 6 3 3 1 3 -4 1
6 -13 -12 7 71 18 31 35 16 7 4 47 2
6 -16 -49 6 32 10 4 25 4 9 14 18 12
0 -5 -9 3 6 2 8 6 0 6 3 1 4
-3 -1 1 3 -1 2 0 0 2 1 -1 0 2
-4 4 2 6 2 6 2 5 6 2 4 -2 5
3 3 -3 4 8 7 2 7 -2 7 -2 2 1
10 13 6 -4 3 -3 -10 -5 -4 3 1 -6 -2
-3 -1 3 -1 0 2 4 6 1 -2 1 1 2
-3 -7 -3 4 7 6 -3 9 4 3 -1 3 2
1 6 4 2 2 4 4 3 3 2 1 0 1
3 1 1 2 3 1 3 4 1 6 5 -2 2
-3 7 0 3 0 3 1 3 1 3 -1 -2 1
-1 8 8 5 -2 3 0 2 -1 4 1 -2 4
-5 2 5 6 1 2 2 -3 -40 1 0 -1 -2
-10 -8 -16 1 -4 -3 -5 -2 -3 6 -5 -10 -12
3 -30 -24 8 36 8 -3 10 2 3 2 23 4
21 -2 -2 -8 8 7 2 10 5 -16 3 -7 -1
-12 -5 5 -1 6 2 -6 1 -5 7 -5 -18 -5
1 -19 -24 10 58 14 1 24 10 5 5 35 -1
-6 1 -75 12 86 23 59 39 9 52 -1 46 6
2 7 3 3 3 3 -3 4 -1 8 -1 -6 -3
-6 3 -3 -4 -7 -4 -7 -2 -3 -6 -5 -4 -3
6 4 2 1 2 4 1 3 0 2 11 2 9
2 4 -2 -1 0 2 0 3 3 1 4 3 12
-1 4 3 1 1 3 -3 3 -1 1 1 -9 1
0 1 -2 1 5 2 -3 4 2 5 2 0 3
-13 -14 -11 -4 -2 -4 -11 -7 -3 -6 -2 -1 -5
9 13 -39 -21 69 7 57 24 20 22 18 58 -32
0 1 -3 6 1 4 -3 3 1 2 2 -1 2
-1 0 2 -2 0 2 1 5 0 4 -1 -2 3
2 -14 -10 -7 0 -1 -1 -1 -1 -5 3 1 1
-9 -8 -7 -2 9 1 12 5 -3 6 -5 -2 -1
0 -4 -2 3 3 3 3 5 1 5 2 1 2
-13 9 -7 0 26 5 17 13 3 73 39 0 -4
-10 3 1 -3 2 4 1 0 0 0 -1 -1 2
-4 -4 2 -2 5 5 -5 3 3 7 2 3 0
-6 4 9 6 1 5 2 5 1 -41 2 0 6
2 3 5 1 1 4 4 1 2 1 -1 2 3
-13 -7 -45 9 83 26 60 45 10 30 3 23 3
3 6 2 -1 3 7 3 5 1 -1 3 12 7
-48 -113 -180 -7 77 1 43 7 9 43 81 48 16
7 -5 -5 4 7 2 0 2 0 7 -2 2 -1
0 2 3 4 3 2 1 3 2 1 3 -2 -1
1 -6 -3 4 -1 3 2 0 0 4 4 2 3
8 9 7 5 -1 3 -4 -1 -3 6 -3 -6 -3
-4 3 5 0 3 2 7 -3 1 4 1 1 2
4 0 1 -2 1 -4 -7 -1 0 0 4 15 4
2 7 3 2 -1 4 0 2 0 0 7 2 5
-2 3 4 2 4 2 7 1 1 3 2 2 7
-3 1 3 -1 2 3 3 3 1 2 0 0 2
4 2 4 2 1 0 1 -2 -1 2 4 3 6
-6 0 -1 5 3 0 2 2 6 2 1 1 3
3 1 2 -11 -1 2 3 3 0 0 3 20 2
-1 -11 -65 14 49 11 20 24 2 34 5 25 0
-7 -4 -6 1 -4 -4 -3 -2 -3 3 -3 -2 1
-11 5 4 4 0 -2 -5 -2 -4 2 -2 -10 -3
-14 -26 -28 -24 14 -14 1 -1 1 4 2 -17 6
2 4 6 1 -1 3 3 2 3 -1 3 -3 5
-8 -8 -11 -5 7 -7 -10 -3 1 0 -1 4 2
-2 3 3 -14 4 6 -3 2 1 12 -2 -4 -1
-3 -4 1 -2 -7 1 1 -3 -3 -6 -1 -6 -2
-4 -28 -47 4 37 2 6 11 2 20 1 0 3
4 -15 -12 18 15 6 44 15 3 3 1 7 2
-2 -2 -6 5 6 4 -3 7 3 -1 1 2 4
-5 -27 -48 7 46 5 14 20 2 20 1 13 -2
-4 2 1 1 3 3 0 0 0 0 5 0 0
-2 4 7 7 -1 4 1 1 1 2 3 0 8
-11 -13 -2 -6 -2 -1 -3 -2 -4 -2 -4 -5 -1
-10 -12 -2 1 3 -3 4 4 -1 3 -3 -7 1
4 5 -1 4 3 0 -2 1 1 3 0 1 3
7 -8 -25 6 25 8 12 7 4 27 7 1 6
-2 1 1 0 2 2 -2 3 1 -1 2 -1 5
2 -20 -17 11 22 9 48 23 3 8 -4 5 0
-2 -8 -5 -5 2 -3 0 -1 0 -4 3 2 -1
-1 3 2 -2 1 -2 0 0 -2 3 0 1 2
-1 1 -2 14 1 3 2 2 2 4 0 3
2 9 2 1 5 2 -1 1 1 4 6 1 3
0 10 2 1 -1 0 1 0 -1 5 3 0 -1
-6 2 -5 0 -1 1 -2 -2 -3 -2 -6 -10 -3
-1 -3 -1 -2 3 4 2 4 2 0 7 -1 -2
-1 -7 -3 1 5 1 0 2 2 1 3 1 -5
4 5 8 3 -1 0 4 1 2 0 4 -2 2
-18 3 -2 2 14 3 -4 6 1 63 19 -23 -5
-2 1 2 0 2 2 3 2 -1 0 1 -3 2
2 -2 3 5 2 4 0 -2 2 1 0 9 7
0 8 4 0 4 4 -1 4 2 3 2 4 2
14 34 -21 20 90 36 79 90 37 53 52 86 14
-18 -12 -5 1 3 6 7 9 11 2 1 -1 3
-7 -5 -10 -5 2 -1 -8 0 -2 -1 1 -2 1
-3 11 1 0 8 6 7 10 3 2 2 16 1
-11 -15 -8 -4 2 0 -2 1 2 -2 0 1 -5
-1 0 3 -1 1 3 0 1 1 -1 2 2 2
-2 0 6 3 1 1 -1 3 1 4 4 -2 2
2 -17 -15 -19 5 -13 -1 0 2 4 2 -13 11
11 2 -5 0 2 2 -1 5 0 3 2 1 4
4 4 12 1 1 6 2 8 2 4 4 -2 0
0 1 0 -1 3 5 2 2 0 1 0 1 1
-7 4 3 5 5 2 1 -5 2 -1 0 -1 -1
1 5 1 4 -1 -1 2 3 1 2 2 2 2
0 -3 -8 0 3 1 -4 1 0 4 -1 7 2
0 -18 -37 10 22 7 -5 6 1 16 1 1 -3
3 4 4 4 3 6 3 -2 2 -2 1 1 2
-4 8 4 5 1 5 2 2 -3 9 1 -1 -6
-2 10 -3 4 4 3 -2 0 -1 4 2 -3 3
7 1 -1 0 2 2 1 2 1 0 -1 5 2
21 12 3 5 6 13 16 19 19 12 13 10 15
-5 0 2 0 0 -2 -2 0 -2 4 2 -3 3
2 2 1 2 3 3 2 6 1 3 2 12 4
3 1 -2 1 2 2 -1 -1 0 0 1 3 3
-1 5 5 7 1 2 0 5 -1 9 4 3 -1
-25 -13 -20 -12 14 9 -4 6 7 -60 11 -3 -23
-7 -5 -12 1 3 2 -1 0 -1 3 2 1 6
3 3 1 1 6 0 -1 3 -1 3 1 3 1
-4 -3 1 -2 -4 -3 -5 -5 -3 -2 0 -6 -1
7 6 -2 2 4 13 11 13 7 -1 1 4 0
-6 2 -1 2 -1 2 1 0 -1 2 -1 -6 -4
-14 -23 -7 3 8 -5 -8 -4 2 6 0 1 3
-23 14 -35 -17 57 8 48 19 11 12 2 26 -22
28 10 7 10 11 13 10 17 20 5 17 23 33
-2 6 2 3 2 1 4 2 3 5 2 -2 -4
5 -5 1 3 3 1 1 3 0 0 2 0 2
-7 -10 -15 4 19 2 2 16 -1 7 -4 -5 1
4 0 3 -1 4 4 3 2 2 5 -1 -2 -3
15 -1 -7 12 18 -1 4 2 3 15 5 38 12
0 5 4 0 1 1 3 0 -2 4 3 -5 3
4 10 -3 -2 5 1 2 1 2 3 3 25 2
-7 -3 -2 9 15 5 -1 4 2 12 7 1 3
-7 -3 -2 -1 7 1 -2 3 3 9 4 -1 12
3 -7 -2 0 2 2 5 4 -1 3 1 -3 -3
0 5 2 1 3 3 0 0 4 2 9 1 7
-1 -13 -7 -1 30 7 18 6 1 10 1 2 0
-4 -1 -2 -1 1 0 -2 -2 -2 3 1 2 23
4 7 7 0 1 1 2 0 2 2 4 -2 -1
9 7 0 -1 4 4 5 12 -1 4 15 8 14
10 -1 2 2 2 3 1 5 0 -3 1 0 8
-39 -96 -137 -20 54 -2 35 2 5 32 68 43 8
-3 -2 0 5 5 5 2 5 1 4 -3 -5 3
14 2 -3 0 7 2 1 4 1 4 1 1 0
0 7 1 0 25 9 14 8 7 3 2 -1 0
-11 0 -1 0 -2 -4 -5 -4 0 -9 -3 -7 -5
-1 -20 -18 2 24 11 2 18 6 20 3 9 16
-24 24 3 1 71 23 60 50 29 54 9 12 -15
2 -1 1 1 2 2 -3 1 -1 1 1 -1 0
3 3 1 3 -1 5 5 7 4 0 -1 -1 -2
2 15 -3 3 10 0 2 1 2 7 2 -6 -2
11 0 -26 1 2 3 0 2 0 -3 2 -1 3
1 -6 -8 9 4 -1 -3 2 1 10 -1 2 -1
-7 -3 4 2 1 4 0 1 1 0 -2 -3 5
-5 -17 -6 -1 1 1 3 4 1 -3 1 4 2
0 3 -1 2 3 -2 2 2 1 2 1 -3 -4
-3 0 3 -19 1 5 3 2 3 2 3 -2 1
5 3 -4 7 20 7 5 9 9 22 7 5 8
0 2 0 -1 3 -2 1 1 -1 2 0 2 1
-22 16 13 0 28 7 11 10 3 21 -1 -3 2
-5 1 1 1 -2 3 2 0 -1 0 0 -2 -2
1 0 -1 1 5 3 0 3 0 1 2 3 5
3 -2 0 2 3 2 -2 0 -1 6 3 -1 1
8 8 4 6 3 4 3 6 3 1 0 -4 3
-8 1 -1 -5 -1 -3 -12 -2 -1 0 -1 -1 0
6 3 2 -2 0 3 1 0 1 0 4 1 0
-2 -2 -2 0 3 3 0 3 1 3 0 0 -2
-20 -2 -2 3 4 3 1 5 6 1 1 0 1
3 -1 2 2 2 2 -5 0 1 -2 1 5 5
-7 -2 -1 0 -2 0 -1 0 -1 1 0 5 1
3 1 2 0 -1 0 -4 -1 0 -3 2 4 3
-7 -16 -5 0 3 -6 -1 1 8 0 -1 3 4
-1 2 6 7 2 4 9 5 2 8 -1 -1 -3
-3 -6 -2 1 2 1 -4 2 0 -1 0 0 2
-4 8 6 6 2 3 -3 1 -2 6 -2 -9 -7
-8 0 1 -2 8 6 16 9 4 51 2 -2 13
11 -14 -12 -4 20 16 25 7 7 29 7 0 7
0 1 1 1 3 2 2 1 1 0 -1 1 0
-2 3 1 4 4 3 1 5 -1 2 4 -3 -2
-1 10 6 1 1 1 2 3 4 2 1 -2 4
9 -5 -5 8 9 2 -4 4 0 13 3 26 5
-7 -5 -3 1 4 -1 1 1 0 -2 0 2 5
-1 -1 -1 0 -1 -1 -2 -2 1 0 1 4 3
-14 -12 -8 -1 13 6 -1 10 0 9 0 -5 -1
-22 -3 -3 1 6 -1 -5 2 0 3 2 -13 2
6 2 2 -5 3 2 -3 0 1 2 2 8 4
-1 -15 -6 -1 2 -6 -3 -3 -2 2 2 -2 -7
5 3 4 -7 1 2 5 4 1 -4 5 4 9
5 7 3 1 4 3 -2 4 2 -1 3 -6 2
-5 -30 -52 8 71 26 55 44 7 28 6 71 17
21 3 5 0 2 3 -1 0 -1 6 6 -4 8
-1 2 2 -1 0 1 -1 1 1 0 2 1 0
3 5 -1 4 4 6 3 3 2 5 6 1 10
4 2 -1 -5 2 4 0 2 -1 2 3 0 1
-1 8 6 -2 1 6 0 3 -3 1 2 -3 0
-3 4 5 -4 0 4 2 4 0 -1 1 -5 4
-17 31 8 30 85 84 92 92 92 34 4 -23 8
-6 -1 0 1 0 1 -12 0 6 0 0 0 -3
0 -4 -1 -4 1 1 0 5 2 0 2 -2 1
-8 7 5 6 2 3 0 -1 3 -1 1 2 1
7 10 5 7 7 7 1 8 10 7 10 15 16
-46 -2 -7 4 15 4 10 11 4 10 -2 -11 -2
9 -7 -5 -5 -1 1 6 -1 1 -6 5 -1 2
1 4 3 -1 4 6 3 5 4 3 -2 0 3
0 -11 -6 4 8 3 -3 0 1 10 -3 1 0
1 2 2 2 1 3 -1 0 -1 0 4 -2 1
0 0 1 -1 -2 4 -2 0 -3 -3 -1 -3 -1
4 -12 -3 8 17 5 1 7 4 13 3 29 7
-1 -3 -3 -2 4 4 -1 5 1 9 0 -1 3
-36 5 -26 7 45 15 60 39 10 34 3 11 -2
0 1 3 1 4 3 2 4 2 0 3 -5 -1
-13 -1 2 7 8 7 12 9 2 49 3 -10 6
HDACs
2 0 12 7 47 11 1 -6
2 1 2 2 2 -3 1 0
4 3 5 3 -5 9 2 3
6 4 3 2 -3 7 1 2
1 1 8 5 28 1 1 -1
-1 0 28 3 34 9 -1 -2
7 2 8 3 1 15 1 -8
-1 1 11 2 29 9 -1 -2
2 2 1 2 6 4 1 1
45 27 5 4 11 14 2 1
92 93 38 4 23 4 7 -12
5 1 5 5 12 12 -17 12
79 53 14 7 9 15 5 0
4 3 5 2 5 17 1 0
3 0 1 3 -6 -2 1 2
92 90 45 3 14 11 5 -7
1 3 7 3 6 8 2 -2
3 3 3 4 9 0 2 1
8 3 2 1 -17 8 2 0
23 13 0 3 3 6 1 0
92 55 9 5 4 18 4 7
16 7 51 -2 27 15 4 -3
-2 -3 -1 -2 -7 3 -2 -5
1 1 3 2 4 12 2 0
64 35 9 5 4 6 1 -3
4 1 3 1 2 13 0 0
2 1 5 4 -5 15 -11 8
7 4 5 1 -1 1 1 3
2 1 1 3 3 3 2 3
0 2 5 3 -6 1 3 4
2 2 6 3 12 -7 0 -3
4 1 2 2 5 -2 2 1
2 2 2 3 4 -2 1 1
6 3 32 4 34 36 2 0
1 -1 3 0 3 0 1 1
3 3 6 7 11 1 1 1
5 6 19 8 23 7 2 1
7 5 4 4 9 5 3 2
2 6 3 6 6 1 2 2
-1 -3 -3 -2 1 -9 -5 0
-1 2 3 2 6 10 0 1
10 6 43 -2 8 15 0 -2
-4 -6 -2 -3 0 0 -3 -3
2 2 5 2 5 7 1 1
5 6 5 0 6 9 1 1
5 8 3 4 -1 10 1 2
-1 -2 -2 -2 -2 1 -2 -2
14 8 11 4 7 8 19 2
3 2 8 3 18 8 7 2
-2 1 6 6 -4 7 1 0
3 4 1 2 2 -3 0 1
0 -1 -2 -2 -4 -1 -3 -4
40 6 46 7 13 10 -1 -1
2 3 4 6 9 2 1 0
0 4 0 2 3 4 0 0
0 1 3 -3 2 -6 1 -2
-3 -4 -4 1 3 -2 -5 -3
3 4 2 3 -2 1 0 2
91 76 2 2 3 3 6 4
1 0 1 3 3 -1 1 0
3 2 20 5 22 25 1 0
4 1 72 19 70 12 0 1
2 1 1 1 2 -15 0 1
3 6 6 -3 -1 -6 1 -1
2 3 33 3 13 0 6 0
92 82 42 1 15 6 9 5
0 0 4 4 9 -19 1 0
3 4 5 6 5 6 0 1
13 7 1 1 6 5 1 1
2 3 2 4 1 11 2 2
4 3 14 7 16 -2 2 1
2 0 1 2 0 5 0 2
2 3 2 3 -2 4 7 2
6 4 69 17 68 33 0 1
3 3 10 10 21 2 2 1
-1 1 0 0 -9 -3 1 0
4 3 1 4 -3 1 2 1
1 1 2 3 6 5 0 -1
0 2 3 1 -1 10 0 2
-2 -4 -4 -1 -8 -5 -5 -4
-4 -2 0 -4 -3 -3 -2 -4
91 62 34 3 14 1 10 4
10 8 3 5 -2 11 12 3
13 9 0 -2 6 0 1 1
4 6 3 5 3 -3 1 1
-5 -3 -2 3 1 -6 -2
2 4 20 1 9 13 1 2
2 3 5 1 -1 4 0 1
3 1 2 2 3 2 1 4
-1 3 3 1 6 8 0 1
2 5 2 3 5 6 1 2
3 3 6 4 11 8 5 2
-2 -3 -1 0 -6 -1 -3 -2
-3 -4 -4 -1 0 -9 -5 -3
1 -2 0 2 -2 -6 1 -2
5 2 8 1 -1 1 3 2
2 2 10 8 14 8 1 5
2 4 3 1 -3 -3 -1 1
-1 1 0 -3 -12 -4 1 0
1 2 2 3 0 6 1 3
3 9 2 6 6 -7 3 0
3 4 5 3 2 4 2 3
3 3 5 4 3 -1 2 3
-1 -2 1 0 -2 -3 -1 -3
4 4 1 4 3 2 2 1
8 5 2 2 1 8 1 2
3 4 2 5 -18 -2 5 0
49 28 3 -1 0 6 2 1
4 5 6 4 12 4 2 -1
2 2 21 5 9 -2 4 1
4 4 15 5 15 13 2 0
84 31 4 5 1 20 2 3
-1 0 5 2 4 1 -8 2
35 18 -1 2 8 3 -3 -4
37 19 3 3 4 1 1 1
13 -3 -1 0 -7 3 1 1
3 1 19 6 35 9 1 1
6 5 3 2 -2 11 2 1
82 50 25 3 9 10 7 3
4 4 5 8 4 13 3 3
3 0 2 0 -1 -8 0 0
4 3 1 4 -1 -1 1 1
4 3 0 5 8 0 1 0
0 1 -1 -1 1 -2 1 1
5 4 0 -3 -3 1 -1 0
-1 2 12 0 -2 1 0 -1
3 3 3 4 -2 4 1 -1
6 4 3 4 0 15 4 -1
1 2 3 2 -3 -6 -1 1
4 1 1 0 3 4 1 -3
5 5 17 4 21 28 21 -3
3 0 2 4 9 5 1 0
1 2 4 3 -1 -5 3 -1
1 -1 -2 -1 -3 0 0 -1
4 2 29 5 45 11 2 -1
98 76 43 0 4 8 1 -3
15 9 2 2 8 4 0 9
4 4 11 4 12 5 1 0
-4 -4 -2 -3 -2 -6 -4 -3
0 -4 3 3 -7 2 3 -3
2 3 4 2 3 4 -1 4
2 0 2 0 -1 5 1 -6
29 5 29 3 6 10 -1 -4
5 3 -100 4 -20 -25 2 -30
2 2 2 2 -8 8 2 0
1 1 2 3 7 1 0 2
7 0 -4 -4 -11 0 -2 -3
3 4 3 4 -5 0 1 2
5 1 8 0 11 5 3 0
2 3 3 3 9 -13 1 1
3 1 2 1 2 6 0 0
1 0 5 2 1 5 2 3
14 11 6 5 1 7 2 3
9 9 -2 2 2 8 1 0
3 3 7 5 10 8 1 2
2 2 10 5 2 8 1 2
-4 -3 2 1 6 2 0 3
3 3 3 3 1 7 2 1
4 5 36 17 65 35 3 2
4 5 1 2 7 -8 0 2
97 89 23 -1 6 2 6 2
3 2 2 3 5 4 2 3
5 6 3 5 5 2 1 2
-1 2 12 0 8 9 2 0
0 0 2 1 2 3 -2 -3
38 11 11 1 -3 -2 3 0
72 28 46 10 -4 8 0 4
2 4 3 0 1 -8 0 1
1 3 2 0 1 -1 1 7
-5 0 6 3 23 7 2 2
1 6 2 5 6 9 2 5
29 3 12 0 13 6 1 1
4 2 1 4 1 3 3 3
1 -4 1 3 4 3 0 -2
1 1 2 1 1 3 1 0
3 3 1 5 5 7 2 2
7 9 7 1 8 11 1 2
0 1 -1 1 2 0 1 1
0 0 0 0 1 1 0 -2
1 2 2 6 3 -7 1 1
4 3 3 10 5 -1 3 7
3 2 4 1 7 1 0 2
6 4 2 5 7 11 2 3
19 11 -2 1 -3 -5 -3 -2
3 3 1 0 3 4 1 2
17 3 2 2 0 -2 1 0
1 0 -2 1 3 -1 -5 -2
2 0 12 3 21 5 1 0
1 3 4 1 4 -4 -1 1
1 3 2 1 -5 -4 0 3
0 -2 -29 3 -5 -1 -1 -15
5 1 17 3 34 -1 5 1
1 2 0 4 4 -11 1 0
3 4 6 3 -2 6 1 -4
8 3 7 3 5 15 1 10
3 4 6 6 2 14 1 1
1 3 0 4 3 3 -1 2
1 2 3 2 -6 3 0 0
1 4 2 0 0 3 0 0
1 1 4 1 -6 12 0 1
10 8 2 3 2 4 -1 6
3 0 6 2 -9 5 4 2
42 23 7 4 13 -8 0 0
5 6 5 3 -4 0 1 -1
3 2 15 5 12 6 8 4
2 -10 -3 0 0 -5 -1 -1
3 3 1 2 0 4 1 0
3 2 3 0 4 1 1 3
0 0 9 1 -2 5 1 6
3 2 66 9 71 39 3 1
2 3 4 2 -14 -17 2 1
10 5 6 5 5 -10 14 0
1 3 2 2 3 -9 0 2
3 4 1 4 -2 11 2 -1
2 1 2 2 1 0 2 -1
31 21 -78 -17 -12 -22 2 -7
0 1 1 -2 4 0 -2 1
3 3 3 -1 8 2 0 1
4 7 2 3 5 4 1 0
3 2 -52 7 -4 10 3 -19
56 30 5 -1 1 -11 1 1
0 -1 0 -4 -4 0 -2 -1
3 6 3 3 5 -14 1 -1
2 -1 1 2 1 3 0 -1
4 3 5 3 1 7 2 3
2 3 4 5 3 9 2 3
2 5 4 1 1 10 0 1
11 10 3 4 3 2 2 1
89 50 16 4 7 9 1 2
3 3 5 2 4 4 1 2
8 4 6 3 0 -8 1 4
Proteases1 -2 0 0 -1 2 0 3
1 1 3 0 3 3 1 -1
2 1 1 1 2 2 1 -3
2 0 1 1 12 2 1 3
0 -4 0 -2 0 0 0 0
-3 1 -2 -4 -3 -1 -2 -6
1 1 -1 0 4 2 1 -3
-4 -2 1 -3 -2 -4 -3 -4
0 1 4 1 3 2 0 0
9 1 4 2 8 5 4 23
92 94 19 96 84 92 95 87
2 2 3 0 5 7 2 3
12 7 6 2 22 14 9 14
0 0 0 0 1 2 -1 -4
1 1 2 0 -4 1 0 -2
90 93 16 93 88 91 94 79
0 4 4 1 0 3 2 4
1 3 2 1 2 3 1 0
2 4 4 0 4 4 1 0
6 2 2 1 9 4 2 8
94 97 20 96 95 100 98 97
12 2 4 50 10 29 6 6
-3 -4 -3 -3 -2 -1 -3 -4
1 2 2 0 4 1 0 0
8 6 7 5 5 8 4 12
1 2 2 4 5 4 3 -1
2 1 3 0 -1 3 1 -2
3 4 0 0 1 5 2 0
0 4 0 0 3 1 1 3
0 2 2 0 0 3 3 0
0 3 -1 -1 3 -1 2 -4
1 4 2 1 1 6 1 6
1 3 2 1 3 2 1 -3
1 2 0 0 5 1 1 2
0 1 1 1 2 1 1 2
2 3 1 1 2 3 1 -1
1 3 -1 0 3 4 3 1
0 5 2 0 3 2 2 1
1 2 4 1 0 1 1 2
-2 -3 -5 -3 -6 -5 -5 -1
0 0 -1 1 2 -1 -1 1
8 1 5 35 6 17 3 2
-5 -6 -2 -2 -7 -4 -5 -10
0 2 1 1 2 3 1 -1
7 2 2 0 5 7 4 4
-1 2 3 2 1 2 1 -1
-4 -4 -3 -2 -4 0 -4 -6
2 4 2 1 -3 4 3 -3
1 4 4 0 1 2 1 1
1 2 0 -1 3 3 2 1
1 1 2 0 3 3 1 -1
-5 -1 -4 -4 -4 -4 -3 -4
90 88 14 85 91 91 93 85
0 2 3 0 8 5 3 1
1 2 1 1 -3 -3 -1 1
0 -6 -1 -1 4 1 -2 2
-3 -1 -4 0 -5 -4 -2 0
1 2 1 1 2 2 1 0
98 93 17 86 86 103 96 93
1 2 2 1 1 3 0 1
1 3 1 0 5 3 0 0
2 0 1 1 5 3 0 4
1 0 2 1 0 1 0 0
6 3 4 1 -25 9 5 8
1 2 0 0 0 0 0 0
95 92 20 91 91 97 93 102
0 3 5 2 4 -1 0 0
1 4 2 1 0 1 1 -2
6 4 3 1 7 9 4 9
0 3 6 2 -3 3 2 8
1 2 9 1 3 4 1 -2
0 -1 0 -2 1 0 -1 -6
1 1 4 0 -2 4 2 2
2 0 4 0 2 5 1 0
1 3 1 5 0 2 -1 2
0 -3 2 0 2 0 -1 -3
1 2 1 0 1 2 1 2
1 -2 1 2 1 0 -3 1
4 1 3 0 4 3 2 6
-2 -1 -3 -4 -7 -6 -4 -2
-4 -5 -3 -2 -7 -3 -4 -4
23 4 6 4 23 17 14 12
3 3 6 3 3 3 1 -5
6 -1 5 2 3 5 2 8
0 1 4 2 -1 5 -1 1
-2 -6 -3 -3 4 -2 -4 -5
3 2 0 1 3 5 1 0
1 2 3 0 -2 4 2 0
0 4 0 0 0 0 -1 1
4 6 4 1 8 6 5 10
1 2 4 0 1 1 1 0
0 3 3 0 0 4 1 2
-4 -3 -1 -3 -2 -7 -4 -1
-3 -1 -2 -3 -3 -3 -3 -3
0 3 1 -1 3 -3 0 -6
3 1 2 0 5 7 1 -1
0 1 1 0 -2 0 1 2
2 2 3 0 0 4 1 -2
0 -4 -3 -2 -2 -1 -1 -1
-1 3 3 1 -1 -1 0 3
0 2 3 4 4 2 1 3
0 3 3 0 -2 3 2 -2
0 4 3 0 3 2 0 -2
-3 -2 -2 -5 -7 -3 0 -3
1 2 1 2 1 4 1 4
6 2 4 2 7 3 2 5
1 3 3 1 4 8 1 -1
89 78 11 52 86 94 96 83
1 3 0 3 -1 4 1 4
0 1 0 0 3 2 2 3
1 0 1 0 3 -1 0 2
93 88 17 87 88 99 97 93
1 0 -1 0 3 -2 0 -4
3 -2 -3 -2 3 1 -1 5
17 15 6 12 75 37 51 16
5 -2 0 -1 -2 3 2 0
1 0 0 1 0 1 0 -1
2 2 2 2 1 3 2 -1
12 4 6 2 12 10 9 5
2 5 2 1 3 5 3 3
0 0 0 3 5 3 0 -2
0 4 2 1 0 -1 1 -1
0 2 2 1 1 -1 -1 0
1 -1 -1 0 0 -1 0 0
2 0 1 0 9 1 0 2
3 1 3 -1 3 3 2 1
1 3 3 3 0 3 -1 2
-1 5 3 1 -2 3 1 4
1 3 2 0 1 4 1 2
1 -2 0 -1 -2 5 0 -3
0 1 3 -1 5 5 0 -6
0 3 0 2 4 0 1 4
0 -1 3 0 0 0 2 -2
0 -3 -2 0 -1 -1 0 -2
2 5 0 2 -1 1 6 1
93 42 14 35 77 62 61 77
2 2 -2 1 3 1 1 3
1 0 1 0 -2 0 -1 -1
-4 -4 -3 -4 -2 -1 -4 -3
-1 -1 -2 -1 0 0 0 -2
1 3 -2 0 3 -1 1 2
3 2 0 0 7 2 1 4
92 75 10 64 82 90 87 89
1 1 0 1 3 6 1 -1
1 2 3 1 -1 5 2 2
0 1 1 1 1 -1 0 4
3 -3 -4 -3 -2 1 -2 -3
0 3 1 1 2 1 1 2
4 2 13 0 3 4 1 3
1 2 3 0 1 2 3 -1
0 -1 2 1 1 2 1 2
2 1 3 3 8 4 1 2
6 4 6 3 6 8 5 2
6 2 4 2 5 3 1 2
0 3 1 0 -2 1 2 -3
1 4 4 -1 2 3 3 0
1 0 1 0 5 2 2 7
0 4 3 0 2 2 2 -1
1 3 2 0 4 4 2 2
1 2 2 0 3 2 2 1
95 84 16 84 93 96 94 85
0 2 2 0 -2 -1 0 1
3 1 2 1 6 4 2 6
1 -3 2 0 -3 -2 1 0
-4 1 -1 -3 -4 -1 2 -2
42 2 5 7 16 32 16 13
93 37 12 47 85 90 67 82
1 2 4 1 3 2 3 0
1 2 3 1 2 4 1 -1
1 1 2 -1 5 2 2 1
2 5 5 2 -1 9 2 5
4 1 1 -1 3 5 1 1
2 3 0 0 -1 2 1 4
0 0 -1 1 5 1 0 -2
1 3 1 3 -1 1 1 1
0 2 4 2 -3 1 0 0
4 3 23 -1 5 6 2 0
0 0 2 5 0 1 -1 -1
2 -2 1 3 7 8 1 4
0 3 2 1 1 -1 1 2
0 4 3 0 -2 5 2 5
1 4 1 1 1 3 2 -2
2 -1 2 0 3 5 1 -4
1 0 -2 -2 -2 0 -2 1
2 0 2 0 -1 4 1 0
4 2 1 1 3 6 2 3
0 0 -2 0 2 -1 -2 3
0 2 0 0 5 1 -1 -3
0 2 0 1 2 1 1 -2
2 0 4 -13 -1 9 0 0
2 0 1 1 0 1 -1 2
2 1 -1 2 0 2 2 4
0 2 1 1 1 -3 0 4
0 5 3 -1 3 2 3 -2
16 2 2 2 7 14 4 5
0 2 -2 0 2 4 2 -5
0 1 0 0 -1 0 4 1
1 4 1 0 2 3 2 0
0 -1 2 1 -2 -1 -1 1
2 2 8 0 0 4 1 -4
1 2 -1 0 4 0 0 0
1 -1 0 0 3 -2 0 -1
56 3 4 3 24 13 11 63
1 -1 -1 1 0 2 0 8
1 -1 2 0 -1 1 1 5
1 -1 -3 0 3 0 1 3
1 0 1 0 2 1 2 1
1 1 1 1 -3 4 0 2
6 1 1 1 7 4 1 4
1 1 0 1 1 2 0 -2
0 1 4 1 3 3 2 1
1 -1 1 1 2 3 2 6
2 1 3 0 1 3 1 1
1 2 3 1 1 4 1 2
1 3 2 0 -4 2 1 1
13 2 4 3 14 14 9 10
1 -5 1 -1 2 1 0 -5
2 3 4 2 2 7 5 5
1 1 3 2 4 4 1 1
1 6 1 0 5 2 1 -6
46 9 2 3 61 21 20 58
1 -1 1 -2 -3 3 0 6
0 3 2 1 4 -1 1 -1
1 4 1 1 -6 1 0 4
1 5 4 1 1 3 2 1
2 4 5 0 3 3 1 0
4 2 1 4 8 5 3 6
4 4 7 1 2 3 2 -2
83 23 4 16 78 65 59 72
1 1 2 -2 -4 0 0 -3
15 2 4 2 9 21 4 3
Phosphatases
79 18 8 25 8 7 5 7 3 4 6 8 13 5 3 6 10 2 3 0 -2 6 13 2 5 4 2 5 3 6 1 0 13 1 1 2 0 -4 1 0 -2 3 0 1 3 -6 -2 1 2 -3 -4 3 1 3 5 7 3 0 -2 1 3 5

19. High Speed Chemistry to Support Iterative Drug Discovery Path
19
Medicinal
chemistry
PK
Off-target
profile
Drug-like
Properties
In vivo testing
Design
(structure
based; etc.)
SynthesisIn vitro testing
Hit Expansion; Hit to Lead
Lead Optimization

20. High Speed Chemistry for Hit Expansion
 Capacity
 Infrastructure allows for purification, drying, analysis, data processing, and custom
formatting of up to 3,000 compounds per week for multiple projects
 Streamlined Purification and QC Operations
 Proprietary automated processes to speed compound flow
 Automated data analyses and reports generation: 100% of deliverables undergo QC
 CLND Quantitation to ensure quality screening results
 We are an innovator in this technology development: Ioana G. Popa-Burke, Olga
Issakova, et. al, Anal Chem (2004) 76, 7278-7287)
20

21. Hit Expansion – Speed and Quality
 Rapid access to starting materials
 In house chemical stock > 60,000 reagents
 Proprietary data base of reagents sourced from proven vendors
 Powerful tools for chemistry team
 5 open access LC-MS (UV/ELSD) systems and open access NMR
 Small molecule X-ray system (Rigaku)
 6 Prep. HPLC and 6 Combiflash systems
 High automation and extensive analytical chemistry capacity
 2 LC/ELSD/MS Quantitation stations (up to 2000 cpds/day)
 4 Automated Mass Triggered HPLC systems for purification
21

22. “Target to Lead” Case Study
Dr. A. Keith Stewart
Vasek and Anna Maria Polak
Professor of Cancer Research
Dean for Research; Mayo Clinic
Innovative Pharmaceutical Solutions for Discovery
Chemistry, Biology and cGMP Manufacturing

23. Modular Approach – Program Milestones
23
• Determined desirable
potency
• Structure–activity
relationship for two
lead series
• Back-up series
• Cell based activity
testing
• Patents filing
Hit to Lead
• Proprietary active series
development
• Structure activity
relationship
• Selectivity testing
Hit expansion
• “Target to Hit” assay
development
• HTS validation
• Fragment screening
• “Smart” HTS utilizing
fragment screening data
Target to hit

24. OBJECTIVES
 Target to hit: Explore if the target is amenable for modulation by small drug-
like organic molecules and identify attractive starting points for tool and lead
compound development
 Timeline – 2.5 months
 Hit expansion and development of new proprietary active series
 Timeline – 3 months
CHALLENGES
 Limited budget
 Tight timeline
24
Case Study - Novel Myeloma Target
• Focus on developing novel IP for composition of matter to attract
pharma partners for further development

25. 2525
Assay development
HTS validation
Fragment
screening
HTS:
Library assembly
and screening
Confirmation
Study
March 20 April 15 May 23 June 8th
“Target-to-Hit” Time Line

26. 0
20
40
60
80
100
Peptide library
Fluorescence
No Enzyme
Plus Enzyme
The Nanosyn peptide library is comprised of ~300 peptides representing potential
natural and artificial substrates for serine/threonine and tyrosine kinases.
Peptide is considered as a candidate substrate if it demonstrates formation of a single
product and at least 50% conversion after 17 hrs of incubation in the presence of
nanomolar-range concentration of enzyme.
26
“Target -to-Hit” Assay Development

27. Vertical Plate Uniformity
0.0000
0.1000
0.2000
0.3000
0.4000
0.5000
0.6000
0 1 2 3 4 5 6 7 8 9 1011121314151617
Wells
Row%Conversion
Left1
Left2
Left3
Middle1
Middle2
Right 1
Right2
Day 1 Day 2 Day 3
Assay stability over 3 days
0.0000
0.1000
0.2000
0.3000
0.4000
0.5000
0.6000
0 2 4 6 8 10
Plates
Raw%Conversion
0% Inhibition
40% Inhibition
100% Inhibition
0% Inhibition control:
0.1 % +/- 1.0%
40% Inhibition control:
43% +/- 2.72%
100% Inhibition control:
99% +/- 1.74%
Z’ = 0.75
Overall statistics
HTS Assay Validation Data
27

28. 28
Confirmed Fragment Hit
Substructure search within
Nanosyn 130K library
~100 HTS
compounds
comprising
this structure
were found
Compounds cherry picked
from 130K and reformatted
to build the focused library
N
N
H
X
R
Fragment Screening to HTS – assembly of focused HTS library

29. Nanosyn HTS 130K compounds diversity library with
selectivity data
29
>20 million data points from screening of 130K HTS Library in 100 HTS
campaigns
In addition to the Fragment-based
approach, the compounds were
selected from the 130K HTS library
based on their selectivity profiles
across ~70 kinases.

30. 30
HTS statistics and confirmation studies results
Total number of HTS compounds tested screened: 30,098
Plate Z’-statistics (n=86): min Z’=0.66, max Z’=0.92, median Z’=0.8
Compound statistics:
Average %-Inhibition : 2.78%
STDEV : 7.82%
3-sigma threshold: 24%
Number of inhibitor hits (above 3s): 438
Number of inhibitor hits (above 6s): 193

31. 31
Series I analysis
 IP position: SciFinder search -very few hits.
 Synthesis: Lack of general synthesis approaches
applicable to a large number of analogs to
explore SAR
 Issues: Potentially reactive - polarized double
bond structure in the seven-membered ring,
exocyclic arrangement of the two double bonds
in the five membered ring
Recommendation: Priority 2
NH
O
OEt
Mayo Series 1

32. 32
Series IV analysis
 IP position:
 Many examples; will need to modify the
scaffold to get an IP position for
composition of matter
 171 refs on 4772 hits. None mention
GRK6; six references include “KINASE”
 Synthesis: straightforward; SAR easy to check
out
Recommendation: Priority 1

33. 1-3 Weeks1-3 Days
3-4 days (80-90%)
Preliminary
Testing
Library
Production
Chemical
Sourcing
Sdfile converted to
location database
Compounds pulled
from in-house storage
(80+%)
33
2-3 Weeks (+5-10%)
Set of 3-6 analogs
All LC-MS checked
Quick optimization
of synthesis and
workup methods
Synthesis Team Workflow – Library of 200 Compounds
 Start with 30-60 compound set
Expand up to 70-100 compound
sets based on synthetic difficulty
 High % checked by LC-MS
 Remove failed compounds
Continued optimization
based on chemistry

34.  Main series:
 Best compound has IC50 79nM.
 180-fold increase in potency over original hit.
 Strong IP position.
 Excellent selectivity (tested against 230 kinases)
 Back-up series:
 Chemically distinct from main series
 Best compound has IC50 309nM. Potential for potency improvement:
 SAR derived from the main series provides additional guidance towards maximizing
potency in this new series.
 Strong IP position
 Excellent selectivity (tested against 59 kinases).
34
Case Study - Conclusions
• Activity improved from 1-20uM to 100nM range
• Two new proprietary active series identified

35. 35
Overview of critical path assays
35
Go / No-go
Development
Decision
hERG
Kinase
screen
Receptor screen
CYP inhibition
In vivo efficacy
model
PgP
Dose escalation /
MTD
Protein binding
PK (i.v. and p.o)
Microsomal
stability
GI 50 cell
assayIC50 in vitro
Solubility /
clogP
Tier 1 Tier 2 Tier 3

36. “Developing Novel IP for Composition of Matter” Case Study
Innovative Pharmaceutical Solutions for Discovery
Chemistry, Biology and cGMP Manufacturing
Eugenia (Jania) Trushina, PhD
Associate Professor
Departments of Neurology
and Pharmacology
Mayo Clinic

37. Existing Inhibitor CP2: Limited Options for Commercialization
37
• Synthetic analog of pyripyropene A, a
potent acyl-CoA : cholesterol O-
acyltransferase inhibitor
• Directly binds to Aβ oligomers
•Reduces levels of Aβ in neurons and
in brain of 5X FAD mice
• Penetrates the blood brain barrier
•EC50=2 uM; cLogP = 1.9
Maezawa et al., J Neurochem, 2006; 98(1) 57; Hong et al., J Neurochem, 2009, 108(4) 1097; Trushina et al., BMC
Neuroscience, 2009, 10:73.
 Short remaining patent life limits the commercial interest to develop this molecule as
a potential therapeutic

38. OBJECTIVES
 Produce novel patentable compounds with properties superior to the
lead compound CP2.
CHALLENGES
 Limited budget (less than $100K per year)
38
Case Study – Developing novel IP for composition of matter
• Focus on developing new proprietary active series and identifying
structural elements necessary for in vitro and in vivo potency

39. Structure Controls Not Only Potency But Also Properties
39
Chemical Structure
Interaction with target Biochemical change
Physicochemical
Properties
Solubility, dosing, delivery
Pharmacokinetic
Properties
Stability, Clearance,
Availability, Distribution
(BBB)
Off-target Interactions Toxicity
S = Biological effect in living systems

40. 40
Hit
Identification
• CP2 Synthesis
• CP2 Evaluation
in Cell-based
assays
• CP2 in Animal
Models
• BBB
Penetration of
CP2
Hit
Expansion
• Structural
Modification of
CP2
• Identify key
pharmacophore
elements
• Baseline SAR
• Evaluate IP
position
Hit to Lead
• Develop
structure-activity
relationship
• Optimize EC50
• In vitro ADME
and BBB
• Selectivity
profiling
Modular Approach – Program Milestones

41. 41
Identification of new CP2-like patentable compounds
% Viability of Ab producing MC65 cells

42. Measured Clearance in Plasma and Brain
42
• C458 Crosses the blood-brain barrier
• With the PK and distribution properties of C458, therapeutic levels of
compound can be reached in the brain

43. C458 treatment protects APP/PS1 animals against cognitive
decline
43
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
DMSO c458 High c458 Low
DISCRIMINATIONINDEX
object 1/2 object n/2
P=0.02
P=0.04
9 months old, treated for 6 months started at 3 months of age

44. Lead optimization – desired properties
Activity ADME Selectivity
• Microsomal stability
(S9) moderate or
low clearance (< 40
mL/mL/mg)
• Predicted BBB
penetration from
MDR1-MDCKII
• hERG IC50>10uM
• Receptor profiling
IC50>10uM
• Kinase profiling
IC50>10uM
• CYP inhibition
<30% inhibition @
10 uM for 3A4, 2D6
• Concentration in
brain > EC50 for at
least 6 hours after
dosing
• EC50 < 0.2 mM
• Safety window for
toxicity in neurons
• Aqueous solubility >
50 mM
44

45.  Four classes of compounds with promising cell protective activity have been identified;
all with strong IP potential.
 Novel Lead Compound C458 recapitulates CP2 mechanism in vitro; superior cell
based activity.
 C458 was tested in APP/PS1 mice and demonstrated efficacy against the
development of AD.
 Patent application is in progress; all IP rights are assigned to Mayo.
45
Case Study - Conclusions
• Novel composition of matter identified by Nanosyn; all IP
belongs to Mayo Clinic

46. Development candidate to IND
46
Through network of
CROs
• CRO performs all
studies and generates
reports
• Follow FDA guidance
IND-enabling studies
At Nanosyn cGMP facility
• Process R&D; demo
batch to demonstrate the
route
• Demo batch can be used
for tox studies
• Analytical development
• Manufacture GMP batch
on a few kg scale. Batch
can be used in Phase I
clinical studies
Manufacturing
IND

47. NANOSYN – Scale-up Services (cGMP and non-GMP)
 Custom synthesis
 From Grams to kilograms
 APIs
 GMP intermediates
 Non-GMP complex building-blocks
 Polymers
 Process R&D
 Scale-up and industrial experienced PhD
chemists
 Analytical method development
IN 2009, NANOSYN FORMED A JOINT VENTURE WITH PCAS, A FRENCH FINE CHEMICAL
AND COMMERCIAL SCALE API MANUFACTURER
47

48. NANOSYN Site Overview
 FDA registered since 1979- strong QA system in place
 cGMP Manufacturing
 Six GMP suites,
 Two class 10,000 clean rooms
 State-of the Art R&D Lab
 Two commercial products
48

49. NANOSYN Has All Pieces to Make your Project Successful
49
Medicinal Chemistry
HTS Platform
Assay
development
cGMP
capabilities

50. Acknowledgements
Nanosyn, Inc.
Kevin Greenman
Sergei Romanov
Olga Issakova
Robert Greenhouse
All Nanosyn team
Mayo Clinic, Rochester, Minnesota
Dr. Keith Stewart
Thank you!
Jania Trushina
Sergey Trushin
Liang Zhang
Mayo Clinic, Scottsdale, Arizona