Your SlideShare is downloading. ×
The Role of High Speed Synthesis in Protein Kinase Approaches Graham F. Smith Library Design and production Group PGRD San...
Kinases - the opportunity <ul><li>There are “433”  kinases </li></ul><ul><ul><ul><li>roles in many diseases </li></ul></ul...
High Speed Synthesis - the opportunity <ul><li>Many of the known pharmacophores fall within existing protocols </li></ul><...
LDP-Sandwich <ul><li>~ 20k compounds per annum </li></ul><ul><ul><ul><li>Sparse / diverse / targeted selections </li></ul>...
IKK2 - HTS to LD POP <ul><li>Simple solution phase chemistry </li></ul><ul><li>PTFE 96 well plates </li></ul><ul><li>Large...
IKK HTS - 1999 UK-374,974  (10.6 µM) UK-379,552 (6.4µM) <ul><li>4880 LDP kinase targeted compounds were present in file </...
IKK2 closed loops
IKK2 - summary <ul><li>HTS produced weak actives from LDP compounds </li></ul><ul><ul><ul><li>poor leads and poor SAR </li...
 
Pyrazoles in cdk2 - Jay Pandit
Kin28 - the next LD POP? <ul><li>MISD target selection/validation </li></ul><ul><li>Evotec HTS assay development </li></ul...
Kin28 1st loop design <ul><li>selected IKK2 and cdk2 compounds </li></ul><ul><li>avoid pyrazole-quinazolines - PGP? </li><...
Other kinase hits <ul><li>Syk </li></ul><ul><ul><ul><li>PILS </li></ul></ul></ul><ul><li>Kin28 - ongoing </li></ul><ul><li...
monomers protocols + = select synthesise screen PGRD core assets  developing competencies expand & beautify apply // synth...
Thanks to... <ul><li>Mark Gardner </li></ul><ul><li>Wolfgang Klute </li></ul><ul><li>Nunzio Sciammetta </li></ul><ul><li>D...
Upcoming SlideShare
Loading in...5
×

The Role of High Speed Synthesis in Protein Kinase Approaches

949

Published on

The Role of High Speed Synthesis in Protein Kinase Approaches, and example of how deverse and purified compound libraries quickly developed leads for IKK2 project

Published in: Career
0 Comments
1 Like
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
949
On Slideshare
0
From Embeds
0
Number of Embeds
1
Actions
Shares
0
Downloads
0
Comments
0
Likes
1
Embeds 0
No embeds

No notes for slide

Transcript of "The Role of High Speed Synthesis in Protein Kinase Approaches"

  1. 1. The Role of High Speed Synthesis in Protein Kinase Approaches Graham F. Smith Library Design and production Group PGRD Sandwich UK
  2. 2. Kinases - the opportunity <ul><li>There are “433” kinases </li></ul><ul><ul><ul><li>roles in many diseases </li></ul></ul></ul><ul><ul><ul><li>known pharmacophores </li></ul></ul></ul><ul><ul><ul><li>known structure motifs - crystal & homology </li></ul></ul></ul><ul><ul><ul><li>large protein ligands </li></ul></ul></ul><ul><ul><ul><li>common ligand ATP </li></ul></ul></ul><ul><li>Weak unselective actives seem common </li></ul><ul><li>Potency, selectivity and novelty efficiently generated are the key LD POP goals </li></ul>
  3. 3. High Speed Synthesis - the opportunity <ul><li>Many of the known pharmacophores fall within existing protocols </li></ul><ul><li>Closed Loop process </li></ul><ul><ul><li>Protocol validation </li></ul></ul><ul><ul><li>Diverse / targeted subsets </li></ul></ul><ul><ul><li>Dedicated production </li></ul></ul><ul><ul><li>HT Screen sequences </li></ul></ul><ul><ul><li>iterative sequence </li></ul></ul><ul><ul><li>IT & communication = oil </li></ul></ul>Design / optimise VL Synthesise Screen Select subset
  4. 4. LDP-Sandwich <ul><li>~ 20k compounds per annum </li></ul><ul><ul><ul><li>Sparse / diverse / targeted selections </li></ul></ul></ul><ul><ul><ul><li>Rule of 5 compliant </li></ul></ul></ul><ul><ul><ul><li>HPLC purified </li></ul></ul></ul><ul><ul><ul><li>QC on every compound </li></ul></ul></ul><ul><li>File enrichment stage completed </li></ul><ul><ul><ul><li>~ 42k compounds registered </li></ul></ul></ul><ul><ul><ul><li>ArQule </li></ul></ul></ul><ul><ul><ul><li>available for HTS </li></ul></ul></ul><ul><ul><ul><li>large VL chemical opportunity </li></ul></ul></ul><ul><li>Closed loop optimisation possible </li></ul>
  5. 5. IKK2 - HTS to LD POP <ul><li>Simple solution phase chemistry </li></ul><ul><li>PTFE 96 well plates </li></ul><ul><li>Large available monomer sets </li></ul>
  6. 6. IKK HTS - 1999 UK-374,974 (10.6 µM) UK-379,552 (6.4µM) <ul><li>4880 LDP kinase targeted compounds were present in file </li></ul><ul><li>delivered a few weak actives from LDP libraries and UK-14,403 </li></ul>UK-379,421 (9.4 µM) UK-14,403 (ca. 2 µM) LDP libraries
  7. 7. IKK2 closed loops
  8. 8. IKK2 - summary <ul><li>HTS produced weak actives from LDP compounds </li></ul><ul><ul><ul><li>poor leads and poor SAR </li></ul></ul></ul><ul><li>closed loop work took place </li></ul><ul><ul><ul><li>6 loops performed </li></ul></ul></ul><ul><ul><ul><li>new monomers added to VL by design after each loop </li></ul></ul></ul><ul><ul><ul><li>VL grew from ~300K to ~4.6 Million </li></ul></ul></ul><ul><ul><ul><li>2.5k compounds made and screened </li></ul></ul></ul><ul><ul><ul><li>~0.5 Chem FTE to complete this work </li></ul></ul></ul><ul><li>TA started lead development project </li></ul><ul><ul><ul><li>LD-POP </li></ul></ul></ul><ul><ul><ul><li>3 structural series - low nM IC50’s </li></ul></ul></ul><ul><ul><ul><li>clear SAR </li></ul></ul></ul><ul><ul><ul><li>whole cell activity in PBMC’s </li></ul></ul></ul>
  9. 10. Pyrazoles in cdk2 - Jay Pandit
  10. 11. Kin28 - the next LD POP? <ul><li>MISD target selection/validation </li></ul><ul><li>Evotec HTS assay development </li></ul><ul><li>Targeted subset pre HTS </li></ul><ul><ul><ul><li>LDP compounds and IKK2 actives found </li></ul></ul></ul><ul><ul><ul><li>cdk2 structure + chimera available </li></ul></ul></ul><ul><ul><ul><li>legacy SAR from IKK2 </li></ul></ul></ul><ul><li>Fungal cidality and selectivity are the key LD-POP goals </li></ul>
  11. 12. Kin28 1st loop design <ul><li>selected IKK2 and cdk2 compounds </li></ul><ul><li>avoid pyrazole-quinazolines - PGP? </li></ul><ul><li>library screened in both IKK2 and Kin28 assays in parallel </li></ul><ul><li>positional scan </li></ul><ul><li>monomers from DISCUS </li></ul><ul><ul><ul><li>Amino alcohols </li></ul></ul></ul><ul><ul><ul><li>pyrazoles and polar hets </li></ul></ul></ul><ul><li>Status…? </li></ul>
  12. 13. Other kinase hits <ul><li>Syk </li></ul><ul><ul><ul><li>PILS </li></ul></ul></ul><ul><li>Kin28 - ongoing </li></ul><ul><li>Cdk2 - selectivity screen </li></ul><ul><li>Lck - ? </li></ul><ul><li>CamKII </li></ul><ul><li>other closed loop gene families </li></ul><ul><li>PDE2, 5, 9, 10 & 11 </li></ul><ul><li>NPFF, mGluR1, MAdCAM, 5HT4 </li></ul>
  13. 14. monomers protocols + = select synthesise screen PGRD core assets developing competencies expand & beautify apply // synthesis to generate LD-POPs Shared VL approach to kinases? AIDD / LiBrain parallel chemistry space
  14. 15. Thanks to... <ul><li>Mark Gardner </li></ul><ul><li>Wolfgang Klute </li></ul><ul><li>Nunzio Sciammetta </li></ul><ul><li>Dave Williams </li></ul><ul><li>Snahel Patel </li></ul><ul><li>Mark Kemp </li></ul><ul><li>Duncan Armour </li></ul><ul><li>Sandy Monaghan </li></ul><ul><li>Martin Edwards </li></ul><ul><li>Pam Greengrass </li></ul><ul><li>Sue Boughton </li></ul><ul><li>John Taylor </li></ul><ul><li>Steve Liu </li></ul><ul><li>Mike Yeadon </li></ul><ul><li>Kate Burt </li></ul><ul><li>Colin Groom </li></ul><ul><li>Rachel Grimley </li></ul><ul><li>Blanda Stammen </li></ul><ul><li>Tanya Parkinson </li></ul>

×