Synthesis and evaluation of substituted hexahydronaphthalenes as novel inhibitors of the Mcl-1/BimBH3 interaction

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:22

Article

Kim, Young B.¹  Balasis, Maria E.¹  Doi, Kenichiro³  Berndt, Norbert¹  DuBoulay, Courtney³  Hu, Chih-Chi Andrew²  Guida, Wayne⁴  Wang, Hong-Gang³  Sebti, Said M.¹  Del Valle, Juan R.¹ 

[1] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Drug Discovery Dept, Tampa, FL 33612 USA

[2] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Immunol, Tampa, FL 33612 USA

[3] Penn State Univ, Dept Pharmacol, Hershey, PA 17033 USA

[4] Univ S Florida, Dept Chem, Tampa, FL 33620 USA

关键词: Mcl-1;    Bcl-2;    Protein-protein interactions;    Small molecule inhibitors;    Anticancer agents;   

DOI  :  10.1016/j.bmcl.2012.07.050

来源: Elsevier

【 摘 要 】

Mcl-1, an anti-apoptotic member of the Bcl-2 protein family, is overexpressed in a broad range of human cancers and plays a critical role in conferring resistance to chemotherapy. In the course of screening a natural product-like library of sesquiterpenoid analogs, we identified substituted hexahydronaphthalenes that showed activity against the Mcl-1/BimBH3 interaction in vitro. Here, we describe the synthesis of a small library of analogs and their biological evaluation. The most potent inhibitor in the series (19) exhibits an IC50 of 8.3 mu M by ELISA and disrupts the interaction between endogenously expressed Mcl-1 and Bim in cultured MDA-MB-468 breast cancer cells. (C) 2012 Elsevier Ltd. All rights reserved.

【 授权许可】

Free