The Effect of Core Replacement on S64315, a Selective MCL-1 Inhibitor, and Its Analogues.

ABSTRACT: Following the identification of thieno[2,3-d]pyrimidine-based selective and potent inhibitors of MCL-1, we explored the effect of core swapping at different levels of advancement. During hit-to-lead optimization, X-ray-guided S-N replacement in the core provided a new vector, whose exploration led to the opening of the so-called deep-S2 pocket of MCL-1. Unfortunately, the occupation of this region led to a plateau in affinity and had to be abandoned. As the project approached selection of a clinical candidate, a series of core swap analogues were also prepared. The affinity and cellular activity of these compounds showed a significant dependence on the core structure. In certain cases, we also observed an increased and accelerated epimerization of the atropoisomers. The most potent

SUBMITTER: Sipos S 

PROVIDER: S-EPMC8412899 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature