7'-substituted benzothiazolothio-and pyridinothiazolothio-purines as potent heat shock protein 90 inhibitors

…, J Shi, M Biamonte, DJ Busch, RE Lough…

Index: Zhang, Lin; Fan, Junhua; Vu, Khang; Hong, Kevin; Le Brazidec, Jean-Yves; Shi, Jiandong; Biamonte, Marco; Busch, David J.; Lough, Rachel E.; Grecko, Roy; Ran, Yingqing; Sensintaffar, John L.; Kamal, Adeela; Lundgren, Karen; Burrows, Francis J.; Mansfield, Robert; Timony, Gregg A.; Ulm, Edgar H.; Kasibhatla, Srinivas R.; Boehm, Marcus F. Journal of Medicinal Chemistry, 2006 , vol. 49, # 17 p. 5352 - 5362

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Citation Number: 83

Abstract

We report on the discovery of benzo-and pyridino-thiazolothiopurines as potent heat shock protein 90 inhibitors. The benzothiazole moiety is exceptionally sensitive to substitutions on the aromatic ring with a 7'-substituent essential for activity. Some of these compounds exhibit low nanomolar inhibition activity in a Her-2 degradation assay (28-150 nM), good aqueous solubility, and oral bioavailability profiles in mice. In vivo efficacy experiments demonstrate ...