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Structure-guided discovery of a selective Mcl-1 inhibitor with cellular activity

DOI: 10.1021/acs.jmedchem.9b00134 DOI Help

Authors: Zoltan Szlávik (Servier Research Institute of Medicinal Chemistry) , Levente Ondi (Servier Research Institute of Medicinal Chemistry) , Márton Csékei (Servier Research Institute of Medicinal Chemistry) , Attila Paczal (Servier Research Institute of Medicinal Chemistry) , Zoltán B. Szabó (Servier Research Institute of Medicinal Chemistry) , Gábor Radics (Servier Research Institute of Medicinal Chemistry) , James Murray (Vernalis (R&D) Ltd) , James Davidson (Vernalis (R&D) Ltd) , Ijen Chen (Vernalis (R&D) Ltd) , Ben Davis (Vernalis (R&D) Ltd) , Roderick E. Hubbard (Vernalis (R&D) Ltd) , Christopher Pedder (Vernalis (R&D) Ltd) , Pawel Dokurno (Vernalis (R&D) Ltd) , Allan Surgenor (Vernalis (R&D) Ltd) , Julia Smith (Vernalis (R&D) Ltd) , Alan Robertson (Vernalis (R&D) Ltd) , Gaetane Letoumelin-braizat (Institute de Recherche Servier) , Nicolas Cauquil (Institute de Recherche Servier) , Marion Zarka (Institute de Recherche Servier) , Didier Demarles (Technologie Servier) , Francoise Perron-sierra (Servier Research Institute of Medicinal Chemistry) , Audrey Claperon (Institute de Recherche Servier) , Frederic Colland (Institute de Recherche Servier) , Olivier Geneste (Institute de Recherche Servier) , András 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: July 2019
Diamond Proposal Number(s): 17182 , 1194 , 2103

Abstract: Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation when observed in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy, has emerged as an attractive target for cancer therapy. Here, we report the discovery of selective small molecule inhibitors of Mcl-1 that inhibit cellular activity. Fragment screening identified thienopyrimidine amino acids as promising but nonselective hits that were optimized using nuclear magnetic resonance and X-ray-derived structural information. The introduction of hindered rotation along a biaryl axis has conferred high selectivity to the compounds, and cellular activity was brought on scale by offsetting the negative charge of the anchoring carboxylate group. The obtained compounds described here exhibit nanomolar binding affinity and mechanism-based cellular efficacy, caspase induction, and growth inhibition. These early research efforts illustrate drug discovery optimization from thienopyrimidine hits to a lead compound, the chemical series leading to the identification of our more advanced compounds S63845 and S64315.

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


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography