3-Substituted-N-(4-hydroxynaphthalen-1-yl)arylsulfonamides As a Novel Class of Selective Mcl-1 Inhibitors: Structure-based Design, Synthesis, SAR, and Biological Evaluation

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2014 Apr 23

PMID 24749893

Citations 33

Authors

Fardokht A Abulwerdi

Chenzhong Liao

Ahmed S Mady

Jordan Gavin

Chenxi Shen

Tomasz Cierpicki

Jeanne A Stuckey

H D Hollis Showalter

Zaneta Nikolovska-Coleska

Affiliations

Soon will be listed here.

Abstract

Mcl-1, an antiapoptotic member of the Bcl-2 family of proteins, is a validated and attractive target for cancer therapy. Overexpression of Mcl-1 in many cancers results in disease progression and resistance to current chemotherapeutics. Utilizing high-throughput screening, compound 1 was identified as a selective Mcl-1 inhibitor and its binding to the BH3 binding groove of Mcl-1 was confirmed by several different, but complementary, biochemical and biophysical assays. Guided by structure-based drug design and supported by NMR experiments, comprehensive SAR studies were undertaken and a potent and selective inhibitor, compound 21, was designed which binds to Mcl-1 with a Ki of 180 nM. Biological characterization of 21 showed that it disrupts the interaction of endogenous Mcl-1 and biotinylated Noxa-BH3 peptide, causes cell death through a Bak/Bax-dependent mechanism, and selectively sensitizes Eμ-myc lymphomas overexpressing Mcl-1, but not Eμ-myc lymphoma cells overexpressing Bcl-2. Treatment of human leukemic cell lines with compound 21 resulted in cell death through activation of caspase-3 and induction of apoptosis.

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