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. (4th February 2016) - Drennen, Brandon
Abstract: 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 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 1 H– 15 N HSQC NMR data. Significantly, inhibitors were easily accessed in just four steps, which will facilitate future optimization efforts. Abstract : 2, 6‐Di‐substituted nicotinates inhibit the myeloid cell leukemia‐1 (Mcl‐1) oncoprotein with potencies in the single‐digit micromolar range, as determined by a fluorescence polarization competition assay. Direct binding to Mcl‐1 was confirmed by 2D 1 H– 15 N HSQC NMR spectroscopy. Inspired by a fragment of a previously reported α‐helix mimetic, the small‐molecules reported herein are more druglike and, owing to greater synthetic accessibility, future optimization is expected to be elementary.