Lee, Taekyu Christov, Plamen P. Shaw, Subrata Tarr, James C. Zhao, Bin Veerasamy, Nagarathanam Jeon, Kyu Ok Mills, Jonathan J. Bian, Zhiguo Sensintaffar, John L. Arnold, Allison L. Fogarty, Stuart A. Perry, Evan E. Ramsey, Haley S. Cook, Rebecca Hollingshead, Melinda Davis Millin, Myrtle Lee, Kyung-min Koss, Brian Budhraja, Amit T. Opferman, Joseph Kim, Kwangho Arteaga, Carlos L. Moore, William J. Olejniczak, Edward T. Savona, Michael R. Fesik, Stephen W. Discovery of Potent Myeloid Cell Leukemia‑1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer 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 (<b>42</b>) that robustly and specifically inhibits Mcl-1 in cell culture and animal xenograft models. Compound <b>42</b> binds to Mcl-1 with picomolar affinity and inhibited growth of Mcl-1-dependent tumor cell lines in the nanomolar range. Compound <b>42</b> 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 <b>42</b> as a potential treatment strategy to block Mcl-1 activity and induce apoptosis in Mcl-1-dependent cancers. myeloid cell leukemia;structure-based design;B cell lymphoma 2 family inhibitors;Mcl -1-dependent cancers;breast cancer xenografts;Compound 42;Mcl -1-dependent tumor cell lines;Human Cancer Overexpression;Mouse Xenograft Models;animal xenograft models 2019-03-30
    https://acs.figshare.com/articles/dataset/Discovery_of_Potent_Myeloid_Cell_Leukemia_1_Mcl-1_Inhibitors_That_Demonstrate_in_Vivo_Activity_in_Mouse_Xenograft_Models_of_Human_Cancer/8001296
10.1021/acs.jmedchem.8b01991.s002