J Med Chem. 2009 Mar 26;52(6):1723-30.

Orally bioavailable antagonists of inhibitor of apoptosis proteins based on an azabicyclooctane scaffold.

Cohen F, Alicke B, Elliott LO, Flygare JA, Goncharov T, Keteltas SF, Franklin MC, Frankovitz S, Stephan JP, Tsui V, Vucic D, Wong H, Fairbrother WJ.

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Departments of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. fcohen@gene.com

Abstract

A series of IAP antagonists based on an azabicyclooctane scaffold was designed and synthesized. The most potent of these compounds, 14b, binds to the XIAP BIR3 domain, the BIR domain of ML-IAP, and the BIR3 domain of c-IAP1 with K(i) values of 140, 38, and 33 nM, respectively. These compounds promote degradation of c-IAP1, activate caspases, and lead to decreased viability of breast cancer cells without affecting normal mammary epithelial cells. Finally, compound 14b inhibits tumor growth when dosed orally in a breast cancer xenograft model.

PMID:: 19228017; [PubMed - indexed for MEDLINE]

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Structures reported by this article

Structure Of An Ml-IapXIAP CHIMERA BOUND TO A Peptidomimetic

PDB: 3F7I

Source: Homo sapiens

Method: X-Ray Diffraction

Resolution: 1.9 Å

See all 3 structures...

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