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Instruments / Technical Area	Publication Details	Published	Actions
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Establishing drug discovery and identification of hit series for the anti-apoptotic proteins, Bcl-2 and Mcl-1 James B. Murray , James Davidson , Ijen Chen , Ben Davis , Pawel Dokurno , Christopher J. Graham , Richard Harris , Allan Jordan , Natalia Matassova , Christopher Pedder , Stuart Ray , Stephen D. Roughley , Julia Smith , Claire Walmsley , Yikang Wang , Neil Whitehead , Douglas S. Williamson , Patrick Casara , Thierry Le Diguarher , John Hickman , Jerome Stark , András Kotschy , Olivier Geneste , Roderick E. Hubbard Acs Omega 4, 8892 - 8906 DOI: 10.1021/acsomega.9b00611 Diamond Proposal Number(s): [671, 1194, 17182] Open Access Show Abstract ▼ Abstract: We describe our work to establish structure- and fragment-based drug discovery to identify small molecules that inhibit the anti-apoptotic activity of the proteins Mcl-1 and Bcl-2. This identified hit series of compounds, some of which were subsequently optimized to clinical candidates in trials for treating various cancers. Many protein constructs were designed to identify protein with suitable properties for different biophysical assays and structural methods. Fragment screening using ligand-observed NMR experiments identified several series of compounds for each protein. The series were assessed for their potential for subsequent optimization using 1H and 15N heteronuclear single-quantum correlation NMR, surface plasmon resonance, and isothermal titration calorimetry measurements to characterize and validate binding. Crystal structures could not be determined for the early hits, so NMR methods were developed to provide models of compound binding to guide compound optimization. For Mcl-1, a benzodioxane/benzoxazine series was optimized to a Kd of 40 μM before a thienopyrimidine hit series was identified which subsequently led to the lead series from which the clinical candidate S 64315 (MIK 665) was identified. For Bcl-2, the fragment-derived series were difficult to progress, and a compound derived from a published tetrahydroquinone compound was taken forward as the hit from which the clinical candidate (S 55746) was obtained. For both the proteins, the work to establish a portfolio of assays gave confidence for identification of compounds suitable for optimization.	May 2019

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I03-Macromolecular Crystallography
I04-Macromolecular Crystallography

Establishing drug discovery and identification of hit series for the anti-apoptotic proteins, Bcl-2 and Mcl-1