Application of chemoproteomics to drug discovery: identification of a clinical candidate targeting hsp90.
A chemoproteomics-based drug discovery strategy is presented that utilizes a highly parallel screening platform, encompassing more than 1000 targets, with a focused chemical library prior to target selection. This chemoproteomics-based process enables a data-driven selection of both the biological target and chemical hit after the screen is complete. The methodology has been exemplified for the purine binding proteome (proteins utilizing ATP, NAD, FAD). Screening of an 8000 member library yielded over 1500 unique protein-ligand interactions, which included novel hits for the oncology target Hsp90. The approach, which also provides broad target selectivity information, was used to drive the identification of a potent and orally active Hsp90 inhibitor, SNX-5422, which is currently in phase 1 clinical studies.
Fadden
Patrick
P
Serenex, Inc., 323 Foster Street, Durham, NC 27701, USA.
Huang
Kenneth H
KH
Veal
James M
JM
Steed
Paul M
PM
Barabasz
Amy F
AF
Foley
Briana
B
Hu
Mei
M
Partridge
Jeffrey M
JM
Rice
John
J
Scott
Anisa
A
Dubois
Laura G
LG
Freed
Tiffany A
TA
Silinski
Melanie A Rehder
MA
Barta
Thomas E
TE
Hughes
Philip F
PF
Ommen
Andy
A
Ma
Wei
W
Smith
Emilie D
ED
Spangenberg
Angela Woodward
AW
Eaves
Jeron
J
Hanson
Gunnar J
GJ
Hinkley
Lindsay
L
Jenks
Matthew
M
Lewis
Meredith
M
Otto
James
J
Pronk
Gijsbertus J
GJ
Verleysen
Katleen
K
Haystead
Timothy A
TA
Hall
Steven E
SE
D000255:Adenosine Triphosphate / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001667:Binding, Competitive; D017321:Clinical Trials, Phase I as Topic; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D040901:Proteomics / Q000379:methods*; D054852:Small Molecule Libraries / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013379:Substrate Specificity
D018841:HSP90 Heat-Shock Proteins; D054852:Small Molecule Libraries; D000255:Adenosine Triphosphate