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

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 calorimet

SUBMITTER: Murray JB 

PROVIDER: S-EPMC6648477 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature