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Instruments / Technical Area	Publication Details	Published	Actions
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Structure-guided discovery of a selective Mcl-1 inhibitor with cellular activity Zoltan Szlávik , Levente Ondi , Márton Csékei , Attila Paczal , Zoltán B. Szabó , Gábor Radics , James Murray , James Davidson , Ijen Chen , Ben Davis , Roderick E. Hubbard , Christopher Pedder , Pawel Dokurno , Allan Surgenor , Julia Smith , Alan Robertson , Gaetane Letoumelin-Braizat , Nicolas Cauquil , Marion Zarka , Didier Demarles , Francoise Perron-Sierra , Audrey Claperon , Frederic Colland , Olivier Geneste , András Kotschy Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b00134 Diamond Proposal Number(s): [17182, 1194, 2103] Show Abstract ▼ 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.	Jul 2019

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I03-Macromolecular Crystallography
I04-Macromolecular Crystallography

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