Combining hit identification strategies: fragment-based and in silico approaches to orally active 2-aminothieno[2,3-d]pyrimidine inhibitors of the Hsp90 molecular chaperone PMID: 19610616

ADC Targets in Oncology

2026-04-10

Combining hit identification strategies: fragment-based and in silico approaches to orally active 2-aminothieno[2,3-d]pyrimidine inhibitors of the Hsp90 molecular chaperone

J Med Chem. 2009 Aug 13;52(15):4794-809. doi: 10.1021/jm900357y.

Paul A Brough ¹ , Xavier Barril , Jenifer Borgognoni , Patrick Chene , Nicholas G M Davies , Ben Davis , Martin J Drysdale , Brian Dymock , Suzanne A Eccles , Carlos Garcia-Echeverria , Christophe Fromont , Angela Hayes , Roderick E Hubbard , Allan M Jordan , Michael Rugaard Jensen , Andrew Massey , Angela Merrett , Antony Padfield , Rachel Parsons , Thomas Radimerski , Florence I Raynaud , Alan Robertson , Stephen D Roughley , Joseph Schoepfer , Heather Simmonite , Swee Y Sharp , Allan Surgenor , Melanie Valenti , Steven Walls , Paul Webb , Mike Wood , Paul Workman , Lisa Wright

Affiliations

Abstract

Inhibitors of the HSP90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of Cancer. Here we describe novel 2-aminothieno[2,3-d]pyrimidine ATP competitive HSP90 inhibitors, which were designed by combining structural elements of distinct low affinity hits generated from fragment-based and in silico screening exercises in concert with structural information from X-ray protein crystallography. Examples from this series have high affinity (IC50 = 50-100 nM) for HSP90 as measured in a fluorescence polarization (FP) competitive binding assay and are active in human Cancer cell lines where they inhibit cell proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Several examples (34a, 34d and 34i) caused tumor growth regression at well tolerated doses when administered orally in a human BT474 human breast Cancer xenograft model.