Rebecca Cook
Faculty Member
Last active: 4/15/2019

Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer.

Lee T, Christov PP, Shaw S, Tarr JC, Zhao B, Veerasamy N, Jeon KO, Mills JJ, Bian Z, Sensintaffar JL, Arnold AL, Fogarty SA, Perry E, Ramsey HE, Cook RS, Hollingshead M, Davis Millin M, Lee KM, Koss B, Budhraja A, Opferman JT, Kim K, Arteaga CL, Moore WJ, Olejniczak ET, Savona MR, Fesik SW
J Med Chem. 2019 62 (8): 3971-3988

PMID: 30929420 · DOI:10.1021/acs.jmedchem.8b01991

Overexpression of myeloid cell leukemia-1 (Mcl-1) in cancers correlates with high tumor grade and poor survival. Additionally, Mcl-1 drives intrinsic and acquired resistance to many cancer therapeutics, including B cell lymphoma 2 family inhibitors, proteasome inhibitors, and antitubulins. Therefore, Mcl-1 inhibition could serve as a strategy to target cancers that require Mcl-1 to evade apoptosis. Herein, we describe the use of structure-based design to discover a novel compound (42) that robustly and specifically inhibits Mcl-1 in cell culture and animal xenograft models. Compound 42 binds to Mcl-1 with picomolar affinity and inhibited growth of Mcl-1-dependent tumor cell lines in the nanomolar range. Compound 42 also inhibited the growth of hematological and triple negative breast cancer xenografts at well-tolerated doses. These findings highlight the use of structure-based design to identify small molecule Mcl-1 inhibitors and support the use of 42 as a potential treatment strategy to block Mcl-1 activity and induce apoptosis in Mcl-1-dependent cancers.

MeSH Terms (20)

Animals Antineoplastic Agents Azepines Binding Sites Cell Line, Tumor Cell Survival Crystallography, X-Ray Drug Evaluation, Preclinical Female Humans Mice Mice, Inbred NOD Mice, SCID Molecular Dynamics Simulation Myeloid Cell Leukemia Sequence 1 Protein Neoplasms Protein Structure, Tertiary Small Molecule Libraries Structure-Activity Relationship Xenograft Model Antitumor Assays

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