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Publication Abstract from PubMed

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.

Discovery of Macrocyclic Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors that Demonstrate Potent Cellular Efficacy and In Vivo Activity in a Mouse Solid Tumor Xenograft Model.,Tarr JC, Jeon K, Veerasamy N, Aichinger M, Salovich JM, Zhao B, Sensintaffar JL, Arnhof H, Wunberg T, Sgubin D, Arnold A, Vekariya RH, Christov PP, Kim K, Fuchs JE, Karier P, Betzemeier B, Van Meveren M, Miriyala N, Olejniczak ET, Engelhardt H, Lee T, McConnell D, Fesik SW J Med Chem. 2025 Sep 11;68(17):18553-18578. doi: 10.1021/acs.jmedchem.5c01376. , Epub 2025 Aug 27. PMID:40864607^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.