Discovery of S64315, a Potent and Selective Mcl-1 Inhibitor.

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Szlavik Z, Csekei M, Paczal A, Szabo ZB, Sipos S, Radics G, Proszenyak A, Balint B, Murray J, Davidson J, Chen I, Dokurno P, Surgenor AE, Daniels ZM, Hubbard RE, Le Toumelin-Braizat G, Claperon A, Lysiak-Auvity G, Girard AM, Bruno A, Chanrion M, Colland F, Maragno AL, Demarles D, Geneste O, Kotschy A

Discovery of S64315, a Potent and Selective Mcl-1 Inhibitor.

J Med Chem. 2020 Nov 25;63(22):13762-13795. doi: 10.1021/acs.jmedchem.0c01234. Epub 2020 Nov 4.

PubMed ID
33146521 [ View in PubMed
]
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.

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