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

DOI: 10.1021/acsomega.9b00611 DOI Help

Authors: James B. Murray (Vernalis (R&D) Ltd) , James Davidson (Vernalis (R&D) Ltd) , Ijen Chen (Vernalis (R&D) Ltd) , Ben Davis (Vernalis (R&D) Ltd) , Pawel Dokurno (Vernalis (R&D) Ltd) , Christopher J. Graham (Vernalis (R&D) Ltd) , Richard Harris (Vernalis (R&D) Ltd) , Allan Jordan (Vernalis (R&D) Ltd) , Natalia Matassova (Vernalis (R&D) Ltd) , Christopher Pedder (Vernalis (R&D) Ltd) , Stuart Ray (Vernalis (R&D) Ltd) , Stephen D. Roughley (Vernalis (R&D) Ltd) , Julia Smith (Vernalis (R&D) Ltd) , Claire Walmsley (Vernalis (R&D) Ltd) , Yikang Wang (Vernalis (R&D) Ltd) , Neil Whitehead (Vernalis (R&D) Ltd) , Douglas S. Williamson (Vernalis (R&D) Ltd) , Patrick Casara (Institut de Recherches Servier Oncology R&D Unit) , Thierry Le Diguarher (Institut de Recherches Servier Oncology R&D Unit) , John Hickman (Institut de Recherches Servier Oncology R&D Unit) , Jerome Stark (Institut de Recherches Servier Oncology R&D Unit) , András Kotschy (Servier Research Institute of Medicinal Chemistry, Hungary) , Olivier Geneste (Institut de Recherches Servier Oncology R&D Unit) , Roderick E. Hubbard (Vernalis (R&D) Ltd; University of York)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acs Omega , VOL 4 , PAGES 8892 - 8906

State: Published (Approved)
Published: May 2019
Diamond Proposal Number(s): 671 , 1194 , 17182

Open Access Open Access

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.

Journal Keywords: Protein identification; Peptides and proteins; Ligands; Crystal structure; Assays

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

Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Other Facilities: ESRF

Added On: 17/07/2019 15:25


Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)