Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design.
Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) are currently generating significant interest in clinical development as potential treatments for cancer. In a preceding publication (DOI: 10.1021/jm100059d ) we describe Astex's approach to screening fragments against Hsp90 and the subsequent optimization of two hits into leads with inhibitory activities in the low nanomolar range. This paper describes the structure guided optimization of the 2,4-dihydroxybenzamide lead molecule 1 and details some of the drug discovery strategies employed in the identification of AT13387 (35), which has progressed through preclinical development and is currently being tested in man.
Woodhead
Andrew J
AJ
Medicinal Chemistry, Astex Therapeutics, Ltd., Cambridge, UK. a.woodhead@astex-therapeutics.com
Angove
Hayley
H
Carr
Maria G
MG
Chessari
Gianni
G
Congreve
Miles
M
Coyle
Joseph E
JE
Cosme
Jose
J
Graham
Brent
B
Day
Philip J
PJ
Downham
Robert
R
Fazal
Lynsey
L
Feltell
Ruth
R
Figueroa
Eva
E
Frederickson
Martyn
M
Lewis
Jonathan
J
McMenamin
Rachel
R
Murray
Christopher W
CW
O'Brien
M Alistair
MA
Parra
Lina
L
Patel
Sahil
S
Phillips
Theresa
T
Rees
David C
DC
Rich
Sharna
S
Smith
Donna-Michelle
DM
Trewartha
Gary
G
Vinkovic
Mladen
M
Williams
Brian
B
Woolford
Alison J-A
AJ
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D005260:Female; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D054833:Isoindoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D008968:Molecular Conformation; D009368:Neoplasm Transplantation; D012995:Solubility; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D001549:Benzamides; D018841:HSP90 Heat-Shock Proteins; D054833:Isoindoles; D008024:Ligands; C552103:(2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanone