Fragment-based discovery of hydroxy-indazole-carboxamides as novel small molecule inhibitors of Hsp90.
Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe the identification of novel small molecular weight inhibitors of Hsp90 using a fragment based approach. Fragments were selected by docking, tested in a biochemical assay and the confirmed hits were crystallized. Information gained from X-ray structures of these fragments and other chemotypes was used to drive the fragment evolution process. Optimization of these high μM binders resulted in 3-benzylindazole derivatives with significantly improved affinity and anti-proliferative effects in different human cancer cell lines.
Merck Serono Research, Merck KGaA, Frankfurter Straße 250, D-64293 Darmstadt, Germany. hans-peter.buchstaller@merckgroup.com
Hans-Peter
HP
Buchstaller
Hans-Michael
HM
Eggenweiler
Christian
C
Sirrenberg
Ulrich
U
Grädler
Djordje
D
Musil
Edmund
E
Hoppe
Astrid
A
Zimmermann
Harry
H
Schwartz
Joachim
J
März
Jörg
J
Bomke
Ansgar
A
Wegener
Michael
M
Wolf
D000577:Amides / Q000737:chemistry* / Q000633:toxicity; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000633:toxicity; D013329:Structure-Activity Relationship
D000577:Amides; D018841:HSP90 Heat-Shock Proteins; D007191:Indazoles; D054852:Small Molecule Libraries