The role of the acidity of N-heteroaryl sulfonamides as inhibitors of bcl-2 family protein-protein interactions

B Barry Touré; Karen Miller-Moslin; Naeem Yusuff; Lawrence Perez; Michael Doré; Carol Joud; Walter Michael; Lucian DiPietro; Simon van der Plas; Michael McEwan; Francois Lenoir; Madelene Hoe; Rajesh Karki; Clayton Springer; John Sullivan; Kymberly Levine; Catherine Fiorilla; Xiaoling Xie; Raviraj Kulathila; Kara Herlihy; Dale Porter; Michael Visser

doi:10.1021/ml300321d

The role of the acidity of N-heteroaryl sulfonamides as inhibitors of bcl-2 family protein-protein interactions

ACS Med Chem Lett. 2013 Jan 4;4(2):186-90. doi: 10.1021/ml300321d. eCollection 2013 Feb 14.

Authors

B Barry Touré¹, Karen Miller-Moslin¹, Naeem Yusuff¹, Lawrence Perez¹, Michael Doré¹, Carol Joud¹, Walter Michael¹, Lucian DiPietro¹, Simon van der Plas¹, Michael McEwan¹, Francois Lenoir¹, Madelene Hoe¹, Rajesh Karki¹, Clayton Springer¹, John Sullivan¹, Kymberly Levine¹, Catherine Fiorilla¹, Xiaoling Xie¹, Raviraj Kulathila¹, Kara Herlihy¹, Dale Porter¹, Michael Visser¹

Affiliation

¹ Novartis Institutes for BioMedical Research Inc. , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.

Abstract

Overexpression of the antiapoptotic members of the Bcl-2 family of proteins is commonly associated with cancer cell survival and resistance to chemotherapeutics. Here, we describe the structure-based optimization of a series of N-heteroaryl sulfonamides that demonstrate potent mechanism-based cell death. The role of the acidic nature of the sulfonamide moiety as it relates to potency, solubility, and clearance is examined. This has led to the discovery of novel heterocyclic replacements for the acylsulfonamide core of ABT-737 and ABT-263.

Keywords: B cell lymphoma; Bcl-2 family; apoptosis; cancer; protein−protein interaction.