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Discovery of S64315, a potent and selective Mcl-1 inhibitor

DOI: 10.1021/acs.jmedchem.0c01234 DOI Help

Authors: Zoltan Szlavik (Servier Research Institute of Medicinal Chemistry) , Marton Csekei (Servier Research Institute of Medicinal Chemistry) , Attila Paczal (Servier Research Institute of Medicinal Chemistry) , Zoltan B. Szabo (Servier Research Institute of Medicinal Chemistry) , Szabolcs Sipos (Servier Research Institute of Medicinal Chemistry) , Gabor Radics (Servier Research Institute of Medicinal Chemistry) , Agnes Proszenyak (Servier Research Institute of Medicinal Chemistry) , Balazs Balint (Servier Research Institute of Medicinal Chemistry) , James 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) , Zoe Marie Daniels (Vernalis (R&D) Ltd) , Roderick E. Hubbard (Vernalis (R&D) Ltd) , Gaëtane Le Toumelin-braizat (Institut de Recherche Servier) , Audrey Claperon (Institut de Recherche Servier) , Gaëlle Lysiak-auvity (Institut de Recherche Servier) , Anne-marie Girard (Institut de Recherche Servier) , Alain Bruno (Institut de Recherche Servier) , Maia Chanrion (Institut de Recherche Servier) , Frédéric Colland (Institut de Recherche Servier) , Ana-leticia Maragno (Institut de Recherche Servier) , Didier Demarles (Technologie Servier) , Olivier Geneste (Institut de Recherche Servier) , Andras Kotschy (Servier Research Institute of Medicinal Chemistry)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: November 2020
Diamond Proposal Number(s): 2103

Abstract: Myeloid cell leukemia 1 (Mcl-1) has emerged as an attractive target for cancer therapy. It is an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we report the discovery of our clinical candidate S64315, a selective small molecule inhibitor of Mcl-1. Starting from a fragment derived lead compound, we have conducted structure guided optimization that has led to a significant (3 log) improvement of target affinity as well as cellular potency. The presence of hindered rotation along a biaryl axis has conferred high selectivity to the compounds against other members of the Bcl-2 family. During optimization, we have also established predictive PD markers of Mcl-1 inhibition and achieved both efficient in vitro cell killing and tumor regression in Mcl-1 dependent cancer models. The preclinical candidate has drug-like properties that have enabled its development and entry into clinical trials.

Journal Keywords: Substituents; Assays; Rodent models; Particulate matter; Tumours

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

Instruments: I02-Macromolecular Crystallography

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