Tetrazole and acylsulfonamide bioisosteric replacements of the carboxylic acid in a dual MCL-1/BCL-xL inhibitor are tolerated

Abstract

Overexpression of the anti-apoptotic protein MCL-1 is associated with a plethora of human cancers, and it reduces the sensitivity of cancer cells to approved chemotherapies. Accordingly, the discovery of MCL-1 inhibitors is an active area of interest. Many inhibitors of the anti-apoptotic MCL-1 protein bear a crucial carboxylic acid that may engage Arg263 in the BH3-binding groove. We previously described the salicylic acid-based dual MCL-1/BCL-x_L inhibitor 17cd, which is currently undergoing lead optimization. As part of that process, we wished to investigate bioisosteric replacement of 17cd's key carboxylic acid. Herein we describe the synthesis of a variety of analogues of a simpler analogue of 17cd presenting carboxylic acid surrogates. The acylsulfonamide and tetrazole motifs, which exhibit comparable pK_as to the carboxylic acid function, displayed similar, or better, binding affinities to MCL-1 and BCL-x_L as the corresponding carboxylic acid-containing lead. Our best compound was acylsulfonamide 7d with a K_i of 800 nM against MCL-1 and 1.82 mM against BCL-x_L, and demonstrated an improved effect on the viability of the HL60 acute myeloid leukemia cell line relative to the parent carboxylic acid-containing dual inhibitor from which it was derived.