9pw6

Myeloid cell leukemia-1 (Mcl-1) complexed with compound 8

spinqualitylabelsall models 9pw6, resolution 2.07Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9pw6 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.068Å Ligands: A1CL3 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function MCL1_HUMAN Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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