Mcl-1 inhibitors(Vanderbilt University School of Medicine)

Myeloid cell leukemia 1 (MCL-1), an antiapoptotic protein, belongs to the BCL-2 protein family and is an extensively studied anticancer target. MCL-1 inhibitors have been in development for decades but fall short on efficacy, toxicity, and side-effects. Recently, Brinkmann et al. shed light on the apoptosis-unrelated function of MCL-1 and its physiological role that could critically lead to MCL-1 inhibitor development.

The B cell lymphoma 2 (Bcl-2) family of proteins are key regulators of intrinsic apoptosis. The antiapoptotic protein myeloid cell leukemia 1 (Mcl-1), which is associated with high tumor grade, poor survival, and resistance to treatment, has emerged as a promising candidate for treating hematological and solid cancers. Herein, we report the structure-guided design of small molecule macrocyclic Mcl-1 inhibitors based on the (R)-methyl-dihydropyrazinoindolone scaffold our group has previously disclosed. The macrocyclic inhibitors bind Mcl-1 with subnanomolar affinity and offer improved potency in cell culture growth inhibition assays. Inhibitor 13 achieved tumor regression in a lung cancer-derived tumor xenograft model in mice as a monotherapy. The improved potency of the macrocyclic series allowed replacement of heretofore conserved indole carboxylic acid moiety, resulting in neutral inhibitors. Amide inhibitor 25 displayed a >10-fold increase in oral bioavailability as compared to acid-containing macrocyclic or acyclic inhibitors.