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

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 core replacement analogues showed
considerable in vivo PD response. One compound was
progressed into efficacy studies and inhibited tumor growth.