Establishing Drug Discovery and Identification of Hit Series for the Anti-apoptotic Proteins, Bcl-2 and Mcl-1

Authors: James B. Murray, James Davidson, I‐Jen Chen, Ben Davis, P. Dokurno, Christopher J Graham, Richard Harris, Allan M. Jordan, Natalia Matassova, C. Pedder, Stuart Ray, Stephen D. Roughley, Julia Smith, C. Walmsley, Yikang Wang, N.E. Whitehead, D.S. Williamson, Patrick Casara, Thierry Le Diguarher, John A. Hickman, Jerome Stark, András Kotschy, Olivier Geneste, Roderick E. Hubbard - ACS Omega 2019 cited by 72

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.