2. Academic Validation
  3. Discovery of S64315, a Potent and Selective Mcl-1 Inhibitor

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.
Zoltan Szlavik 1,  Marton Csekei 1,  Attila Paczal 1,  Zoltan B Szabo 1,  Szabolcs Sipos 1,  Gabor Radics 1,  Agnes Proszenyak 1,  Balazs Balint 1,  James Murray 2,  James Davidson 2,  Ijen Chen 2,  Pawel Dokurno 2,  Allan E Surgenor 2,  Zoe Marie Daniels 2,  Roderick E Hubbard 2,  Gaëtane Le Toumelin-Braizat 3,  Audrey Claperon 3,  Gaëlle Lysiak-Auvity 3,  Anne-Marie Girard 3,  Alain Bruno 3,  Maia Chanrion 3,  Frédéric Colland 3,  Ana-Leticia Maragno 3,  Didier Demarles 4,  Olivier Geneste 3,  Andras Kotschy 1
Affiliations

Affiliations

  • 1 Servier Research Institute of Medicinal Chemistry, Záhony u. 7, H-1031 Budapest, Hungary.
  • 2 Vernalis (R&D) Ltd., Granta Park, Cambridge CB21 6GB, U.K.
  • 3 Institut de Recherche Servier, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France.
  • 4 Technologie Servier, 27 Rue Eugène Vignat, 45000 Orleans, France.
PMID: 33146521 DOI: 10.1021/acs.jmedchem.0c01234
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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