2. Academic Validation
  3. 7'-substituted benzothiazolothio- and pyridinothiazolothio-purines as potent heat shock protein 90 inhibitors

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

  • J Med Chem. 2006 Aug 24;49(17):5352-62. doi: 10.1021/jm051146h.
Lin Zhang 1,  Junhua Fan,  Khang Vu,  Kevin Hong,  Jean-Yves Le Brazidec,  Jiandong Shi,  Marco Biamonte,  David J Busch,  Rachel E Lough,  Roy Grecko,  Yingqing Ran,  John L Sensintaffar,  Adeela Kamal,  Karen Lundgren,  Francis J Burrows,  Robert Mansfield,  Gregg A Timony,  Edgar H Ulm,  Srinivas R Kasibhatla,  Marcus F Boehm
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Conforma Therapeutics Corporation, 9393 Towne Centre Drive, Suite 240, San Diego, California 92121, USA. [email protected]
PMID: 16913725 DOI: 10.1021/jm051146h
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 that compounds of this class inhibit tumor growth in an N87 human colon Cancer xenograft model via oral administration as shown with compound 37 (8-(7-chlorobenzothiazol-2-ylsulfanyl)-9-(2-cyclopropylamino-ethyl)-9H- purin-6-ylamine).

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