6bw2
Mcl-1 complexed with small molecules
Structural highlights
FunctionMCL1_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.[1] Publication Abstract from PubMedMyeloid cell leukemia 1 (Mcl-1), an anti-apoptotic member of the Bcl-2 family of proteins, has emerged as an attractive target for cancer therapy. Mcl-1 upregulation is often found in many human cancers and is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we describe a series of potent and selective tricyclic indole diazepinone Mcl-1 inhibitors that were discovered and further optimized using structure-based design. These compounds exhibit picomolar binding affinity and mechanism-based cellular efficacy, including growth inhibition and caspase induction in Mcl-1 sensitive cells. Thus, they represent useful compounds to study the implication of Mcl-1 inhibition in cancer and serve as potentially useful starting points toward the discovery of anti-Mcl-1 therapeutics. Optimization of Potent and Selective Tricyclic Indole Diazepinone Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors Using Structure-Based Design.,Shaw S, Bian Z, Zhao B, Tarr JC, Veerasamy N, Jeon K, Belmar J, Arnold AL, Fogarty SA, Perry E, Sensintaffar JL, Camper DV, Rossanese OW, Lee T, Olejniczak ET, Fesik SW J Med Chem. 2018 Jan 11. doi: 10.1021/acs.jmedchem.7b01155. PMID:29323899[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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