Discovery of potent heterodimeric antagonists of inhibitor of apoptosis proteins (IAPs) with sustained antitumor activity

  • J Med Chem. 2015 Feb 12;58(3):1556-62. doi: 10.1021/jm501482t.
Heidi L Perez  1 ,  Charu Chaudhry ,  Stuart L Emanuel ,  Caroline Fanslau ,  Joseph Fargnoli ,  Jinping Gan ,  Kyoung S Kim ,  Ming Lei ,  Joseph G Naglich ,  Sarah C Traeger ,  Ragini Vuppugalla ,  Donna D Wei ,  Gregory D Vite ,  Randy L Talbott ,  Robert M Borzilleri
Affiliations
  • 1. Bristol-Myers Squibb Research , P.O. Box 4000, Princeton, New Jersey 08543, United States.
PMID: 25584393 DOI: 10.1021/jm501482t
Abstract

The prominent role of IAPs in controlling cell death and their overexpression in a variety of cancers has prompted the development of IAP antagonists as potential antitumor therapies. We describe the identification of a series of heterodimeric antagonists with highly potent antiproliferative activities in cIAP- and XIAP-dependent cell lines. Compounds 15 and 17 further demonstrate curative efficacy in human melanoma and lung Cancer xenograft models and are promising candidates for advanced studies.