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The effect of core replacement on S64315, a selective MCL-1 inhibitor, and its analogues

DOI: 10.1021/acsomega.1c02595 DOI Help

Authors: Szabolcs Sipos (Servier Research Institute of Medicinal Chemistry) , Balázs Bálint (Servier Research Institute of Medicinal Chemistry) , Zoltán B. Szabó (Servier Research Institute of Medicinal Chemistry) , Levente Ondi (Servier Research Institute of Medicinal Chemistry) , Márton Csékei (Servier Research Institute of Medicinal Chemistry) , Zoltán Szlávik (Servier Research Institute of Medicinal Chemistry) , Ágnes Proszenyák (Servier Research Institute of Medicinal Chemistry) , James B. Murray (Vernalis (R&D) Ltd) , James Davidson (Vernalis (R&D) Ltd) , Ijen Chen (Vernalis (R&D) Ltd) , Pawel Dokurno (Vernalis (R&D) Ltd) , Allan E. Surgenor (Vernalis (R&D) Ltd) , Christopher Pedder (Vernalis (R&D) Ltd) , Roderick E. Hubbard (Vernalis (R&D) Ltd) , Ana-Leticia Maragno (Institut de Recherches Servier) , Maia Chanrion (Institut de Recherches Servier) , Frederic Colland (Institut de Recherches Servier) , Olivier Geneste (Institut de Recherches Servier) , András Kotschy (Servier Research Institute of Medicinal Chemistry)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acs Omega , VOL 6 , PAGES 22073 - 22102

State: Published (Approved)
Published: August 2021
Diamond Proposal Number(s): 1857

Open Access Open Access

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

Journal Keywords: Reaction products; Mixtures; Inhibitors; Nitrogen; Molecular structure

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 13/10/2021 09:17

Documents:
acsomega.1c02595.pdf

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Cancer Drug Discovery Non-Communicable Diseases Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)