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Tethered
Hsp90/HtpG
inhibitor
Hsp90 or HtpG
Targeting Hsp90 and its pathogen
Orthologs with Tethered Inhibitors as a
Diagnostic and Therapeutic Strategy for
cancer and infectious diseases.
Timothy Haystead Ph.D.
Professor of Pharmacology and
Cancer Biology Duke University.
Serenex 2000 – 2008 Durham NC
SNX-5422 oral inhibitor of Hsp90
 Multiple Phase 1 solid tumor
 Progressed through Phase 2
 Approved for phase 3 registration trials 2019
Drugs in clinical trials Haystead lab
HS-196 – novel imaging agent for the detection of
metastatic disease (2017)
https://clinicaltrials.gov/ct2/show/NCT03333031
HS-201, an HSP90 Inhibitor-linked Verteporfin for
Detection of Solid Malignancies (2019)
https://clinicaltrials.gov/ct2/show/NCT03906643
EydisBio Inc. Durham NC
2020-
Development
TAK-1 kinase inhibitors
Corporate Head Quarters
G23 Protein URA1
G24
glutamate synthase
(NADH)
H13
H14
H15 Alpha-aminoadipate reductase
H16
phosphoribosylformylglycinamidine
synthase
H17
H18 Elongation factor 3
H19
H20
6-
phosphofructokinase
Trifunctional formate-tetrahydrofolate
ligase
methenyltetrahydrofolate
cyclohydrolase
oxoglutarate dehydrogenase
H21
6-
phosphofructokinase
Cell division control protein 48
H22
Phosphoribosylformylglycinamidine cyclo-
ligase
H23 Heat shock protein 90
H24 Heat shock protein 90
I13 Heat shock protein 90
I14 Transketolase 1
Heat shock protein 90
I15
Heat shock protein
SSB1
I16
I17 Inosine-5'-monophosphate dehydrogenase
I18
Elongation factor 1-
alpha 2
I19 Actin ACT_CANAX
Elongation factor Tu
Obg-like ATPase 1
I20
Mannose-1-phosphate
guanyltransferase
Pyruvate
dehydrogenase E1
Chorismate synthase
I21
Pyruvate
dehydrogenase E1
I22 Glyceraldehyde-3-phosphate dehydrogenase
I23
40S ribosomal protein S0
RSSA_CANAL
Clathrin light chain
Kerat
ins
A. B.
C.
Drug Discovery Programs in the Haystead Lab
HS-10
HS-72
HS-106
HS-38
Target: Hsp90
Indications:-
 Metastatic cancers
 HIV
Target: DAP Kinases
PIM Kinases
Indications:-
 Cardiovascular
 Cancer
Target: Hsp70i
Indications:-
 Cancer
 Antiviral
Target: Fatty acid Synthase
Indications:-
 Cancer
 Antiviral
 Obesity
Target: TAK1
Indications:-
 Cancer
 autoimmune
Cell Chem Biol. 2017 Aug 17;24(8):1029-1039
Sci Rep 2018 Nov 19;8(1):17058
Arthritis Res Ther 2019 Dec 17;21(1):292
J Biol Chem. 2020 Feb 7;295(6):1565-1574
Oncotarget. 2020 May 26;11(21):1961-1970
ACS Chem Biol 2022 Mar 18;17(3):536-544
JCI Insight 2023 8 (14)
J Pain 2023 Apr 29;S1526-5900(23)00402-9
Antiviral Res. 2014 Mar;103:7-16
Antimicrob Agents Chemother 2018 27;62(4) ACS Chem Biol. 2013 Dec 20;8(12):2715-23
Cell Chem Biol. 2018 Oct 18;25(10):1195-1207
Exp Physiol 2023 Jul;108(7):986-997.
Cell Chem Biol. 2014 Dec 18;21(12):1648-59
Antiviral Res. 2016 Jun;130:81-92
Tethered inhibitors.
Cell Chem Biol 2023 in press
Pain 2022 Jun 1;163(6):1091-1101.
Sci Rep 2022 Oct 27;12(1):18091
Mol Cancer Ther 2022 Jan;21(1):217-226
Nature Commun Biol. 2020 May 8;3(1):226
Clin Cancer Res. 2017 Dec 15;23(24):7531-7542
ACS Chem Biol. 2017 Apr 21;12(4):1047-1055
Cell Chem Biol. 2013 Sep 19;20(9):1187-97.
Cell Chem Biol. 2016 Jun 23;23(6):678-88
Retrovirology. 2017 Sep 29;14(1):45
J Biol Chem 2021 Nov;297(5):101272.
A
Figure 1
B GFP-Hsp90a
GFP-BbHtpG C
D
E
KD BX-2819 12 ±5.8nM
KD SNX5422 167 ± 0.146µM
KD BX-2819 16.4 ± 6nM
KD SNX5422 26.8 ± 1.31nM
D74
2.4
3.7
H87
3.8
K41
3.5
2.7
T166
3.8
2.9
2.7
F121
3.7
3.3
G78
3.0
2.8
A38
3.8
I77
3.6
M79
4.2
3.5
N34
4.0
2.7
3.0
w
w
w
BX-2819
3.2
BX-
2819
Asn34
Lys41
Asp74
Thr166
Gly78
Val133
Leu88
Phe121
His87
BX-
2819
Asn51
Lys58
Asp93
Thr184
Gly97
Val150
Leu107
Phe138
BbHtpG
Hsp90
0.1 1 10 100
0
50
100
Log [Drug] µM
%
GFP
protein
fluoresence
0.1 1 10 100
0
50
100
Log [Drug] µM
%
GFP
protein
fluoresence
Co-crystal Redinbo Lab
Mark Kowalewski
Adam D. Lietzan
GFP-HTPG
1 10 100 1000 10000
1
10
100
1000
10000
Hsp90 KD
HtpG
K
D
Hsp90 vs HtpG Kd
287
288
289
292
293
295
299
298
297
296
300
301
303
304
305
306
308
310
311
312
313
314
315
317
318 319
320
321
322
323324
325
326
327
328
329
330
331
334
335
336
337
338
343
344
350
351
353
355
356
357
358
Equipotency Line
HS Compound
Affinity bias for HtpG
Affinity bias for Hsp90
A
B
1 10 100 1000
0
200000
400000
600000
800000
1000000
Log[HS-drug]µM
GFP
fluoresence
HS463vHsp90,Grp94,BbHtpG
Hsp90
Grp94
BbHtpG
A New Iterative campaign defines HS-463 a Bb HtpG inhibitor that discriminates BbHtpG from Hsp90 and Grp94.
nM
1 10 100 1000
0
200000
400000
600000
800000
1000000
Log[HS-drug]µM
GFP
protein
all v 463
B. burgdorferi
T. denticola
T. pallidum
Leptospiria
Contacts made by BX-2819 in Borrelia HtpG
Bb HtpG
fraction
1 2 3 4 5 Extract
flow
through
HS-463 affinity resin
0.001 0.01 0.1 1 10
0
100000
200000
300000
400000
500000
600000
700000
Log[HS-drug]µM
GFPBbHtpG
CHEMISTRY PLATFORM
N
N
O
N
H
O
H2N
N
N
O
N
H
O NH2
O
O
O
O
O
Near IR
820 nm
780 nm
640 nm
FITC
FITC + I
iodine
spin label
itself
magnetic beads
gold nanoparticle
toxin
methotrexate
Gd chelate
delivery agent
affinity resin
Hsp90
inhibitor
X
biotin
N
N
O
N
H
H2N O
O
O
O
O
O N
H
O
O
O
O
O
N
H
O
S
NH
HN
O
PDT verteporfin
Imaging Agent
Linker
Domain
Enzyme Specific
Targeting Ligand
Keq, surface
TARGETING PLASMA EXTRACELLULAR HSP90 WITH TETHERED INHIBITORS
Ectopic Hsp90
 Associated with malignancy
 Antibodies to Hsp90 block migration
Tsutsumi S, Neckers L. Extracellular heat shock
protein 90: a role for a molecular chaperone in cell
motility and cancer metastasis. Cancer Sci.
2007;98(10):1536-9.
Fluor-tethered Hsp90 Inhibitors Discriminate Various Tumor Lines
Jarred Barrott (Cell Chem Bio. 2013).
HS-27
Video shows 3D confocal analysis of HS-131 uptake
BT474 and then MDA-MB 468 cells
Normal cells Tumor cells
Representative 2D Images
Brightfield
Fluorescence
(exp = 2000
ms)
Bright field and fluorescence (em640nm) cryo-sectioned mouse bearing flank tumor
m#1 m#2 m#3 m#4 m#1 m#2 m#3 m#4
HS196 HS199
MDA-MB-231 Tumor Imaging with nIR-Hsp90 Inhibitor: HS196 vs. HS199
Pre-inj
immediate
3 h
6 h
12 h
24 h
48 h
168 h
Images provided by Takuya Osada Duke University)
Side 1 Side 2
LI-COR Pearl
FLUOBEAM
Photograph
Image analyzed by
Image Studio software
Image analyzed by
Image J software
Images of a patient prostate tumor
administered 2 mg HS-196
Audience Poll
Ligand Tether Payload
Fluorophore
Iodine
Chelate
Ga68 Ce134 A225
eHsp90
inhibitor
I124
I131
PET- Enabled Tethered inhibitors of eHsp90.
Gall bladder
secondary tumor
Bowel
Large Tumor
Tumor
PET images comparing the biodistribution 18FDG and 124I labeled
HS-113 in the MMTV model of HER2+ breast cancer.
(B) PET
124I HS113
(A) PET
18FDG
Lymph
secondary tumor
Gall bladder
secondary
tumor
Bowel
Primary
Tumor
(B) PET
124I HS-113
(A)
PET
18FDG
Lymph
secondary
tumor
Kidney
Heart
Bladder
Brain
media cell
0
2000
4000
6000
8000
Uptake DOTA-Tethered Hsp90
inhibitor into MDA-231 cells
Cpm
Ce-134
(June 12, 2024) Webinar: Development of PET theranostics targeting the molecular chaperones eHsp90 and HtpG for cancer and infectious disease
O
H2N
N
H
O
O
O
O
O
N
N
O
N
N
N
N
N
N
N
O O
N
O
O
H2N H
N
O O
O O
O
N
N
O
O
La
HS-561
N
N
O
N
H
O
H2N
O
O
O
O
O N
H
O
O
N N
O OH
O
O
O
O
O
Fe
H
HS-560
CO2H
HO2C
N
N
O
N
H
O
H2N
O
O
O
O
O N
H
N
N
O
OH
O
OH
OH
HS-559
O
H2N
N
H
O
O
O
O
O N
N
N
O
N
N
N
N
O
N
N
O
O
O O
La
HS-556
N
H
N
N
N
N
O
N
N
HO O
O
O
O
O
O
O
O
O
N
H
O
H
N
O
H2N
F F
F
O
N
H
O
O
O
O
O
O
O
O
O
N
H
HN
H2N
O
F
F
F
HS-548
N
H
N
N
N
N
O
N
N
O
OH
HO O
O
O
O
O
O
O
O
O
N
H
O
H
N
O
H2N
F F
F
HS-547
H
N
N
N N N
N O
OH
O
N
HO O
O
O O
O
O
O
O
O
O
NH
N
HN
N
S
HO
HO
HS-544
N
N
N N
N
O
OH
O
N O
OH
O
H
N
H
N
H2N O
O
O
O
O
HS-542
N
H
N
N
N
N
O
N
N
O
OH
HO O
O
O
O
O
O
O
O
O
N
H
O
H
N
O
H2N
HS-543
O
H2N
N
H
O
O
O
O
O N
H
N
N
O
N
N
N
N
O
N
N
O
OH
HO O
HS-530
NH
HN
H2N
O
O
O
O
N
O
O
N
N
N
N
N
O
O
N
N Cu
O
O
HS-529
OH
N
N
OH
O
N
HO
O
N
N
H
O
O
O
O
O
O
O
O
N
H
H
N
H2N O
O O
O
HS-410
N
H
O
O
O
O
O N
H
O
N
N OH
O
N
OH
O
N
HO
O
N O
N
N
O
HS-334
OH
HO
N
N
NH
S
N
H
O
O
O
O
O
O
O
O
O
N
H
N
O
N
N
N
HO O
O
OH
O
OH
HS-324
N
H
O
O
O
O
O N
H
O
N
N O
O
N
O
O
N
O
O
H2N O
N
N
O
Gd
HS-37
Structures of chelate tethered Hsp90/HtpG inhibitors. HS-561to HS-556, HS-530, HS-334 to HS-37
target human and fungal Hsp90. HS-548 to HS-542, HS-529, HS-410, HS-324 target bacterial HtpG.
1 10 100 1000
0
500000
1000000
1500000
2000000
µM drug
GFPHsp90
GFPHsp90vHS530-HS603
HS10
HS463
HS530
HS538
HS559
HS542
HS547
HS603
O
H2N
N
H
O
O
O
O
O N
H
N
N
O
N
N
N
N
O
N
N
O
OH
HO O
CO2H
HO2C
N
N
O
N
H
O
H2N
O
O
O
O
O N
H
N
N
O
OH
O
OH
OH
HS-530
HS-559
(June 12, 2024) Webinar: Development of PET theranostics targeting the molecular chaperones eHsp90 and HtpG for cancer and infectious disease
O
H2N
N
H
O
O
O
O
O N
H
N
N
O
N
N
N
N
O
N
N
O
OH
HO O
0.1 1 10 100 1000
0
200000
400000
600000
800000
1000000
pmol HS530
cpm
Ce-134
Exp 7 titration Sep Pak
HS530 Sep Pak bound
Flow through
6
0
m
i
n
6
0
m
i
n
L
P
S
1
2
0
m
i
n
1
2
0
m
i
n
L
P
S
2
4
0
m
i
n
L
P
S
0
200000
400000
600000
PBMC ± LPS HS530 Ce-134
time uptake PBMC
HS-530
Ce-134
cpm
notes - lost 240 min control unstimulated
Uptake HS-530/Ce134 into PBMC ± 2µM LPS
0 50 100 150 200 250
0
5000
10000
15000
20000
time min
HS-559
cpm
Uptake HS595 in MDA 231 cells
Infectious Disease
Prepared by Matt Redinbo UNC.
Uptake of HS-542/Ce-134 into Borrelia burgdorferi in culture
Imlytics software
ACKNOWLEDGEMENTS
Haystead Lab (Duke)
Philip Hughes
David Carlson
David Alcorta
David Gooden
Khaldon Bodoor
Lauren Crowe
Jared Barrott
David Loiselle
Isaac Lutz
Kelly Yang
Lucas Dingman
Sawyer Lyons
Zoe Dingman.
Victoria Parker
Jo Jo Farina
Collaborators.
UNC
Matt Redinbo
Hong Yuan
Tulane
Monica Embers
Stanford
Christine Jacobs Wagner
Duke
Kim Lyerly
Takuya Osada
Neil Spector
Mark Oldham
UC Davis U. Delaware (TEM/Storm)
Shannon Modla
Jean Ross
Jeff Caplan
Emir Hodzic
Funding.
NIH
DOD
Openphilanthropy.org
***Cohen Foundation
Bill & Marian Cook
Foundation
***Bay Area Lyme
OpenPhilantropy
Q&A
WWW.SCINTICA.COM
INFO@SCINTICA.COM
Please enter your questions
in the Q&A section
Thank You!

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  • 2. Serenex 2000 – 2008 Durham NC SNX-5422 oral inhibitor of Hsp90  Multiple Phase 1 solid tumor  Progressed through Phase 2  Approved for phase 3 registration trials 2019 Drugs in clinical trials Haystead lab HS-196 – novel imaging agent for the detection of metastatic disease (2017) https://clinicaltrials.gov/ct2/show/NCT03333031 HS-201, an HSP90 Inhibitor-linked Verteporfin for Detection of Solid Malignancies (2019) https://clinicaltrials.gov/ct2/show/NCT03906643 EydisBio Inc. Durham NC 2020- Development TAK-1 kinase inhibitors Corporate Head Quarters
  • 3. G23 Protein URA1 G24 glutamate synthase (NADH) H13 H14 H15 Alpha-aminoadipate reductase H16 phosphoribosylformylglycinamidine synthase H17 H18 Elongation factor 3 H19 H20 6- phosphofructokinase Trifunctional formate-tetrahydrofolate ligase methenyltetrahydrofolate cyclohydrolase oxoglutarate dehydrogenase H21 6- phosphofructokinase Cell division control protein 48 H22 Phosphoribosylformylglycinamidine cyclo- ligase H23 Heat shock protein 90 H24 Heat shock protein 90 I13 Heat shock protein 90 I14 Transketolase 1 Heat shock protein 90 I15 Heat shock protein SSB1 I16 I17 Inosine-5'-monophosphate dehydrogenase I18 Elongation factor 1- alpha 2 I19 Actin ACT_CANAX Elongation factor Tu Obg-like ATPase 1 I20 Mannose-1-phosphate guanyltransferase Pyruvate dehydrogenase E1 Chorismate synthase I21 Pyruvate dehydrogenase E1 I22 Glyceraldehyde-3-phosphate dehydrogenase I23 40S ribosomal protein S0 RSSA_CANAL Clathrin light chain Kerat ins A. B. C.
  • 4. Drug Discovery Programs in the Haystead Lab HS-10 HS-72 HS-106 HS-38 Target: Hsp90 Indications:-  Metastatic cancers  HIV Target: DAP Kinases PIM Kinases Indications:-  Cardiovascular  Cancer Target: Hsp70i Indications:-  Cancer  Antiviral Target: Fatty acid Synthase Indications:-  Cancer  Antiviral  Obesity Target: TAK1 Indications:-  Cancer  autoimmune Cell Chem Biol. 2017 Aug 17;24(8):1029-1039 Sci Rep 2018 Nov 19;8(1):17058 Arthritis Res Ther 2019 Dec 17;21(1):292 J Biol Chem. 2020 Feb 7;295(6):1565-1574 Oncotarget. 2020 May 26;11(21):1961-1970 ACS Chem Biol 2022 Mar 18;17(3):536-544 JCI Insight 2023 8 (14) J Pain 2023 Apr 29;S1526-5900(23)00402-9 Antiviral Res. 2014 Mar;103:7-16 Antimicrob Agents Chemother 2018 27;62(4) ACS Chem Biol. 2013 Dec 20;8(12):2715-23 Cell Chem Biol. 2018 Oct 18;25(10):1195-1207 Exp Physiol 2023 Jul;108(7):986-997. Cell Chem Biol. 2014 Dec 18;21(12):1648-59 Antiviral Res. 2016 Jun;130:81-92 Tethered inhibitors. Cell Chem Biol 2023 in press Pain 2022 Jun 1;163(6):1091-1101. Sci Rep 2022 Oct 27;12(1):18091 Mol Cancer Ther 2022 Jan;21(1):217-226 Nature Commun Biol. 2020 May 8;3(1):226 Clin Cancer Res. 2017 Dec 15;23(24):7531-7542 ACS Chem Biol. 2017 Apr 21;12(4):1047-1055 Cell Chem Biol. 2013 Sep 19;20(9):1187-97. Cell Chem Biol. 2016 Jun 23;23(6):678-88 Retrovirology. 2017 Sep 29;14(1):45 J Biol Chem 2021 Nov;297(5):101272.
  • 5. A Figure 1 B GFP-Hsp90a GFP-BbHtpG C D E KD BX-2819 12 ±5.8nM KD SNX5422 167 ± 0.146µM KD BX-2819 16.4 ± 6nM KD SNX5422 26.8 ± 1.31nM D74 2.4 3.7 H87 3.8 K41 3.5 2.7 T166 3.8 2.9 2.7 F121 3.7 3.3 G78 3.0 2.8 A38 3.8 I77 3.6 M79 4.2 3.5 N34 4.0 2.7 3.0 w w w BX-2819 3.2 BX- 2819 Asn34 Lys41 Asp74 Thr166 Gly78 Val133 Leu88 Phe121 His87 BX- 2819 Asn51 Lys58 Asp93 Thr184 Gly97 Val150 Leu107 Phe138 BbHtpG Hsp90 0.1 1 10 100 0 50 100 Log [Drug] µM % GFP protein fluoresence 0.1 1 10 100 0 50 100 Log [Drug] µM % GFP protein fluoresence Co-crystal Redinbo Lab Mark Kowalewski Adam D. Lietzan
  • 7. 1 10 100 1000 10000 1 10 100 1000 10000 Hsp90 KD HtpG K D Hsp90 vs HtpG Kd 287 288 289 292 293 295 299 298 297 296 300 301 303 304 305 306 308 310 311 312 313 314 315 317 318 319 320 321 322 323324 325 326 327 328 329 330 331 334 335 336 337 338 343 344 350 351 353 355 356 357 358 Equipotency Line HS Compound Affinity bias for HtpG Affinity bias for Hsp90 A B
  • 8. 1 10 100 1000 0 200000 400000 600000 800000 1000000 Log[HS-drug]µM GFP fluoresence HS463vHsp90,Grp94,BbHtpG Hsp90 Grp94 BbHtpG A New Iterative campaign defines HS-463 a Bb HtpG inhibitor that discriminates BbHtpG from Hsp90 and Grp94. nM 1 10 100 1000 0 200000 400000 600000 800000 1000000 Log[HS-drug]µM GFP protein all v 463 B. burgdorferi T. denticola T. pallidum Leptospiria Contacts made by BX-2819 in Borrelia HtpG
  • 9. Bb HtpG fraction 1 2 3 4 5 Extract flow through HS-463 affinity resin 0.001 0.01 0.1 1 10 0 100000 200000 300000 400000 500000 600000 700000 Log[HS-drug]µM GFPBbHtpG
  • 10. CHEMISTRY PLATFORM N N O N H O H2N N N O N H O NH2 O O O O O Near IR 820 nm 780 nm 640 nm FITC FITC + I iodine spin label itself magnetic beads gold nanoparticle toxin methotrexate Gd chelate delivery agent affinity resin Hsp90 inhibitor X biotin N N O N H H2N O O O O O O N H O O O O O N H O S NH HN O PDT verteporfin
  • 11. Imaging Agent Linker Domain Enzyme Specific Targeting Ligand Keq, surface TARGETING PLASMA EXTRACELLULAR HSP90 WITH TETHERED INHIBITORS Ectopic Hsp90  Associated with malignancy  Antibodies to Hsp90 block migration Tsutsumi S, Neckers L. Extracellular heat shock protein 90: a role for a molecular chaperone in cell motility and cancer metastasis. Cancer Sci. 2007;98(10):1536-9.
  • 12. Fluor-tethered Hsp90 Inhibitors Discriminate Various Tumor Lines Jarred Barrott (Cell Chem Bio. 2013). HS-27
  • 13. Video shows 3D confocal analysis of HS-131 uptake BT474 and then MDA-MB 468 cells
  • 15. Representative 2D Images Brightfield Fluorescence (exp = 2000 ms) Bright field and fluorescence (em640nm) cryo-sectioned mouse bearing flank tumor
  • 16. m#1 m#2 m#3 m#4 m#1 m#2 m#3 m#4 HS196 HS199 MDA-MB-231 Tumor Imaging with nIR-Hsp90 Inhibitor: HS196 vs. HS199 Pre-inj immediate 3 h 6 h 12 h 24 h 48 h 168 h Images provided by Takuya Osada Duke University)
  • 17. Side 1 Side 2 LI-COR Pearl FLUOBEAM Photograph Image analyzed by Image Studio software Image analyzed by Image J software Images of a patient prostate tumor administered 2 mg HS-196
  • 19. Ligand Tether Payload Fluorophore Iodine Chelate Ga68 Ce134 A225 eHsp90 inhibitor I124 I131 PET- Enabled Tethered inhibitors of eHsp90.
  • 20. Gall bladder secondary tumor Bowel Large Tumor Tumor PET images comparing the biodistribution 18FDG and 124I labeled HS-113 in the MMTV model of HER2+ breast cancer. (B) PET 124I HS113 (A) PET 18FDG Lymph secondary tumor Gall bladder secondary tumor Bowel Primary Tumor (B) PET 124I HS-113 (A) PET 18FDG Lymph secondary tumor Kidney Heart Bladder Brain
  • 21. media cell 0 2000 4000 6000 8000 Uptake DOTA-Tethered Hsp90 inhibitor into MDA-231 cells Cpm Ce-134
  • 23. O H2N N H O O O O O N N O N N N N N N N O O N O O H2N H N O O O O O N N O O La HS-561 N N O N H O H2N O O O O O N H O O N N O OH O O O O O Fe H HS-560 CO2H HO2C N N O N H O H2N O O O O O N H N N O OH O OH OH HS-559 O H2N N H O O O O O N N N O N N N N O N N O O O O La HS-556 N H N N N N O N N HO O O O O O O O O O N H O H N O H2N F F F O N H O O O O O O O O O N H HN H2N O F F F HS-548 N H N N N N O N N O OH HO O O O O O O O O O N H O H N O H2N F F F HS-547 H N N N N N N O OH O N HO O O O O O O O O O O NH N HN N S HO HO HS-544 N N N N N O OH O N O OH O H N H N H2N O O O O O HS-542 N H N N N N O N N O OH HO O O O O O O O O O N H O H N O H2N HS-543 O H2N N H O O O O O N H N N O N N N N O N N O OH HO O HS-530 NH HN H2N O O O O N O O N N N N N O O N N Cu O O HS-529 OH N N OH O N HO O N N H O O O O O O O O N H H N H2N O O O O HS-410 N H O O O O O N H O N N OH O N OH O N HO O N O N N O HS-334 OH HO N N NH S N H O O O O O O O O O N H N O N N N HO O O OH O OH HS-324 N H O O O O O N H O N N O O N O O N O O H2N O N N O Gd HS-37 Structures of chelate tethered Hsp90/HtpG inhibitors. HS-561to HS-556, HS-530, HS-334 to HS-37 target human and fungal Hsp90. HS-548 to HS-542, HS-529, HS-410, HS-324 target bacterial HtpG.
  • 24. 1 10 100 1000 0 500000 1000000 1500000 2000000 µM drug GFPHsp90 GFPHsp90vHS530-HS603 HS10 HS463 HS530 HS538 HS559 HS542 HS547 HS603 O H2N N H O O O O O N H N N O N N N N O N N O OH HO O CO2H HO2C N N O N H O H2N O O O O O N H N N O OH O OH OH HS-530 HS-559
  • 26. O H2N N H O O O O O N H N N O N N N N O N N O OH HO O 0.1 1 10 100 1000 0 200000 400000 600000 800000 1000000 pmol HS530 cpm Ce-134 Exp 7 titration Sep Pak HS530 Sep Pak bound Flow through
  • 27. 6 0 m i n 6 0 m i n L P S 1 2 0 m i n 1 2 0 m i n L P S 2 4 0 m i n L P S 0 200000 400000 600000 PBMC ± LPS HS530 Ce-134 time uptake PBMC HS-530 Ce-134 cpm notes - lost 240 min control unstimulated Uptake HS-530/Ce134 into PBMC ± 2µM LPS
  • 28. 0 50 100 150 200 250 0 5000 10000 15000 20000 time min HS-559 cpm Uptake HS595 in MDA 231 cells
  • 30. Prepared by Matt Redinbo UNC.
  • 31. Uptake of HS-542/Ce-134 into Borrelia burgdorferi in culture Imlytics software
  • 32. ACKNOWLEDGEMENTS Haystead Lab (Duke) Philip Hughes David Carlson David Alcorta David Gooden Khaldon Bodoor Lauren Crowe Jared Barrott David Loiselle Isaac Lutz Kelly Yang Lucas Dingman Sawyer Lyons Zoe Dingman. Victoria Parker Jo Jo Farina Collaborators. UNC Matt Redinbo Hong Yuan Tulane Monica Embers Stanford Christine Jacobs Wagner Duke Kim Lyerly Takuya Osada Neil Spector Mark Oldham UC Davis U. Delaware (TEM/Storm) Shannon Modla Jean Ross Jeff Caplan Emir Hodzic Funding. NIH DOD Openphilanthropy.org ***Cohen Foundation Bill & Marian Cook Foundation ***Bay Area Lyme OpenPhilantropy
  • 33. Q&A WWW.SCINTICA.COM INFO@SCINTICA.COM Please enter your questions in the Q&A section Thank You!

Editor's Notes

  1. ----- Meeting Notes (10/24/11 10:25) ----- This slide shows the new version of the old proteome mining assay. We now tagg all the proteins on the media with fluor probes. This enables highly quantitative sensitive screening without using a mass spec. It has been important in the fluor and paramagnetic probe development to ensure that modifying the 90 inhibitors does not alter affinity for Hsp90 or alter the selectivity within the entire purinome.
  2. ----- Meeting Notes (10/24/11 10:27) ----- lustrates the general concept of using targeted ligands to detect malignant cells in vivo. The imaging agent could be paramagnetic or fluor probe.
  3. Fixed cells were imaged with a fluorescent microscope. Negative control consists of the well treated with a drug and then imaged with the opposite fluorescence filters (i.e. cells treated with HS-27 and looked at with the Cy5 filter). Drug concentrations are at 100 nM.
  4. Example of a longitudinal cross section of the entire mouse – HS-131 is found in the tumor and gut lumen. Injection artifact is also shown in the tail region.