Open AccessDiscovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods
Author(s) -
Nicholas F. Pelz,
Zhiguo Bian,
Bin Zhao,
Subrata Shaw,
James C. Tarr,
Johannes Belmar,
Claire Gregg,
DeMarco V. Camper,
Craig M. Goodwin,
Allison L. Arnold,
John Sensintaffar,
Anders Friberg,
Olivia W. Rossanese,
Min Ho Lee,
Edward T. Olejniczak,
Stephen W. Fesik
Publication year - 2016
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.5b01660
Subject(s) - chemistry , myeloid leukemia , indole test , small molecule , leukemia , programmed cell death , apoptosis , binding site , plasma protein binding , computational biology , cancer research , stereochemistry , biochemistry , genetics , biology
Myeloid cell leukemia-1 (Mcl-1) is a member of the Bcl-2 family of proteins responsible for the regulation of programmed cell death. Amplification of Mcl-1 is a common genetic aberration in human cancer whose overexpression contributes to the evasion of apoptosis and is one of the major resistance mechanisms for many chemotherapies. Mcl-1 mediates its effects primarily through interactions with pro-apoptotic BH3 containing proteins that achieve high affinity for the target by utilizing four hydrophobic pockets in its binding groove. Here we describe the discovery of Mcl-1 inhibitors using fragment-based methods and structure-based design. These novel inhibitors exhibit low nanomolar binding affinities to Mcl-1 and >500-fold selectivity over Bcl-xL. X-ray structures of lead Mcl-1 inhibitors when complexed to Mcl-1 provided detailed information on how these small-molecules bind to the target and were used extensively to guide compound optimization.