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Structural Re‐engineering of the α‐Helix Mimetic JY‐1‐106 into Small Molecules: Disruption of the Mcl‐1–Bak‐BH3 Protein–Protein Interaction with 2,6‐Di‐Substituted Nicotinates
Author(s) -
Drennen Brandon,
Scheenstra Jacob A.,
Yap Jeremy L.,
Chen Lijia,
Lanning Maryanna E.,
Roth Braden M.,
Wilder Paul T.,
Fletcher Steven
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500461
Subject(s) - chemistry , helix (gastropod) , small molecule , microbiology and biotechnology , biology , biochemistry , ecology , snail
The disruption of aberrant protein–protein interactions (PPIs) with synthetic agents remains a challenging goal in contemporary medicinal chemistry but some progress has been made. One such dysregulated PPI is that between the anti‐apoptotic Bcl‐2 proteins, including myeloid cell leukemia‐1 (Mcl‐1), and the α‐helical Bcl‐2 homology‐3 (BH3) domains of its pro‐apoptotic counterparts, such as Bak. Herein, we describe the discovery of small‐molecule inhibitors of the Mcl‐1 oncoprotein based on a novel chemotype. Particularly, re‐engineering of our α‐helix mimetic JY‐1‐106 into 2,6‐di‐substituted nicotinates afforded inhibitors of comparable potencies but with significantly decreased molecular weights. The most potent inhibitor 2‐(benzyloxy)‐6‐(4‐chloro‐3,5‐dimethylphenoxy)nicotinic acid ( 1 r : K i =2.90 μ m ) likely binds in the p2 pocket of Mcl‐1 and engages R263 in a salt bridge through its carboxylic acid, as supported by 2D 1 H– 15 N HSQC NMR data. Significantly, inhibitors were easily accessed in just four steps, which will facilitate future optimization efforts.