Mcl-1 inhibitors(Vanderbilt University School of Medicine)

Introducing and integrating functional assays into clinical cancer care can further enhance the effectiveness of precision cancer medicine. Bcl-2 pro-survival proteins have emerged as promising targets across various cancers, with Venetoclax, a highly selective Bcl-2 inhibitor, being the first approved drug of this category. This study aims to explore BH3 profiling as a functional diagnostic to distinguish pro-survival dependence in a variety of human cancers to identify antiapoptotic Bcl-2 family protein dependencies and sensitivity to BH3 mimetics. The obtained results demonstrate that, in general, hematological cancer cell lines are sensitive to Bcl-2 or Mcl-1 inhibitors. Notably, certain lymphoma subtypes of B-cell and T-cell origin show preferential dependence on Bcl-2 and Mcl-1, respectively. These conclusions were supported and enhanced by follow-up studies of primary patient-derived samples. Immunohistochemistry of patient specimens supported the identified overexpression and functional involvement of Bfl-1 in T-cell lymphomas, highlighting a new potential precision therapy opportunity. Functional profiling of various solid tumor cell lines, including ovarian cancer PDX models, revealed that most solid tumors have a dependence on a combination of Bcl-2 family antiapoptotic proteins. Treatment with a combination of Bcl-xL and Mcl-1 inhibitors induced significant apoptosis in a majority of the tested solid tumor cell lines. The results of this study reveal a functional dependence on Bcl-2 antiapoptotic proteins in various cancers and offer more tailored strategies for utilizing BH3 mimetics in precision cancer therapy.

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.