1‐Sulfonylated 1,2,3,4‐tetrahydroquinoline‐6‐carboxylic acids as simple, readily‐accessible MCL‐1 inhibitors

Abstract

MCL‐1 is a member of the BCL‐2 family of proteins that regulates the mitochondrial pathway of apoptosis. Overexpression of MCL‐1 is associated with the development and progression of a range of human cancers, and is also responsible for the onset of resistance to conventional chemotherapies. Although several MCL‐1 inhibitors have now advanced to clinical trials, recent suspensions and terminations reveal the urgency with which new inhibitor chemotypes must be discovered. Building on our previous studies of a chiral, isomeric lead, we report the discovery of a new chemotype to inhibit MCL‐1: 1‐sulfonylated 1,2,3,4‐tetrahydroquinoline‐6‐carboxylic acid. The nature of the sulfonyl moiety contributed significantly to the resulting inhibitory ability. For example, transforming a phenylsulfonyl group into a 4‐chloro‐3,5‐dimethylphenoxy)phenyl)sulfonyl moiety elicited more than a 73‐fold enhancement in inhibiton of MCL‐1, possibly through targeting the p2 pocket in the BH3‐binding groove, and so it is anticipated that further structure‐activity studies here will lead to continued improvements in binding. It should be underscored that this class of MCL‐1 inhibitors is readily accessible in four simple steps, is achiral and offers many avenues for optimization, all factors that are welcomed in the search for safe and effective inhibitors of this driver of cancer cell survival.

Discovery of N-sulfonylated aminosalicylic acids as dual MCL-1/BCL-xL inhibitors

“…We previously reported a class of MCL-1 inhibitors – herein discovered to be selective for MCL-1 over BCL-xL – based on chiral 1-sulfonamido-THQ-3-carboxylic acids. Subsequent isomerization to the achiral 1-sulfonamido-THQ-6-carboxylic acid counterparts 27 followed by deconstructing the piperidine-type ring to afford 4-sulfonamidobenzoic acid derivatives resulted in moderately potent MCL-1 inhibitors, but none bound MCL-1 as tightly as the original THQ (±)- 4 . Nevertheless, the simpler 4-sulfonamidobenzoic acid scaffold permitted more facile diversification with greater commercial availabilities of precursors.…”

“…2), although this led to a significant decrease in MCL-1 binding affinity ( K i = 2.73 μM). 27 In the structure of the 6-THQ scaffold, the nitrogen atom is fused in the THQ ring, restricting the ability to alter the N -alkyl component, and modification of the phenyl ring is not trivial. To overcome these barriers to further optimization of the 6-THQ series, we decided to re-engineer the 6-THQ scaffold by deconstructing the piperidine-type ring, thereby transforming the core into a 4-aminobenzoic acid scaffold ( e.g.…”