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

Brandon Drennen; Jacob A. Scheenstra; Jeremy L. Yap; Lijia Chen; Maryanna E. Lanning; Braden M. Roth; Paul T. Wilder; Steven Fletcher

doi:10.1002/cmdc.201500461

journal article Open Access Feb 04, 2016

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

Brandon Drennen Jacob A. Scheenstra Jeremy L. Yap Lijia Chen

Maryanna E. Lanning Braden M. Roth Paul T. Wilder Steven Fletcher

ChemMedChem Vol. 11 No. 8 pp. 827-833 · Wiley

View at Publisher Save 10.1002/cmdc.201500461

Abstract

AbstractThe 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: Ki=2.90 μm) likely binds in the p2 pocket of Mcl‐1 and engages R263 in a salt bridge through its carboxylic acid, as supported by 2D 1H–15N HSQC NMR data. Significantly, inhibitors were easily accessed in just four steps, which will facilitate future optimization efforts.

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Details

Published: Feb 04, 2016
Vol/Issue: 11(8)
Pages: 827-833
License: View

Authors

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Brandon Drennen