Structure-Guided Discovery of a Selective Mcl-1 Inhibitor with Cellular Activity

摘要: Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family proteins, whose upregulation when observed in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy, has emerged as attractive target for cancer therapy. Here, we report discovery selective small molecule inhibitors Mcl-1 that inhibit cellular activity. Fragment screening identified thienopyrimidine amino acids promising but nonselective hits were optimized using nuclear magnetic resonance X-ray-derived structural information. The introduction hindered rotation along a biaryl axis conferred selectivity compounds, activity was brought on scale by offsetting negative charge anchoring carboxylate group. obtained compounds described here exhibit nanomolar binding affinity mechanism-based efficacy, caspase induction, growth inhibition. These early research efforts illustrate drug optimization from lead compound, chemical series leading identification our more advanced S63845 S64315.