C. Pedder

TL;DR: It is demonstrated that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway.

TL;DR: S55746 administered by oral route daily in mice demonstrated robust anti-tumor efficacy in two hematological xenograft models with no weight lost and no change in behavior, demonstrating that S55746 is a novel, well-tolerated BH3-mimetic targeting selectively and potently the BCL-2 protein.

TL;DR: The discovery of selective small molecule inhibitors of Mcl-1 that inhibit cellular activity is reported, and the obtained compounds described here exhibit nanomolar binding affinity and mechanism-based cellular efficacy, caspase induction, and growth inhibition.

TL;DR: This 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 identified hit series of compounds, some of which were subsequently optimized to clinical candidates in trials for treating various cancers.

TL;DR: The discovery, biochemical and biophysical characterization of these probes including small molecule ligand co-crystal structures with Polθ are described and crystallographic data provides a basis for understanding the unique mechanism of inhibition of these compounds which is dependent on stabilization of a "closed" enzyme conformation.