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
  • 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.