Open AccessThe Effect of Core Replacement on S64315, a Selective MCL-1 Inhibitor, and Its Analogues
Author(s) -
Szabolcs Sipos,
Balázs Bálint,
Zoltán Szabó,
Levente Ondi,
Márton Csékei,
Zoltán Szlávik,
Ágnes Proszenyák,
James B. Murray,
James Davidson,
IJen Chen,
P. Dokurno,
A.E. Surgenor,
C. Pedder,
Roderick E. Hubbard,
Ana-Leticia Maragno,
Maïa Chanrion,
Frédéric Colland,
Olivier Geneste,
András Kotschy
Publication year - 2021
Publication title -
acs omega
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.779
H-Index - 40
ISSN - 2470-1343
DOI - 10.1021/acsomega.1c02595
Subject(s) - epimer , chemistry , core (optical fiber) , lead compound , in vivo , stereochemistry , combinatorial chemistry , pyrimidine , pharmacology , computational biology , biochemistry , in vitro , biology , computer science , microbiology and biotechnology , telecommunications
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.