The structure guided discovery of a selective Mcl-1 inhibitor with cellular activity

Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation when observed in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy, has emerged as an attractive target for cancer therapy. Here we report the discovery of selective small molecule inhibitors of Mcl-1 that inhibit cellular activity. Fragment screening identified thienopyrimidine amino acids as a promising but non-selective hit that were optimized using NMR and X-ray derived structural information. The introduction of hindered rotation along a biaryl axis has conferred high selectivity to the compounds and cellular activity was brought on scale by offsetting the negative charge of the anchoring carboxylate group. The obtained compounds exhibit nanomolar binding affinity and mechanism-based cellular efficacy, caspase induction and growth inhibition. Thus, they are considered as potential leads toward the discovery of anti-Mcl-1 therapeutics.