%0 Generic %A Lee, Taekyu %A Christov, Plamen P. %A Shaw, Subrata %A Tarr, James C. %A Zhao, Bin %A Veerasamy, Nagarathanam %A Jeon, Kyu Ok %A Mills, Jonathan J. %A Bian, Zhiguo %A Sensintaffar, John L. %A Arnold, Allison L. %A Fogarty, Stuart A. %A Perry, Evan %A E. Ramsey, Haley %A S. Cook, Rebecca %A Hollingshead, Melinda %A Davis Millin, Myrtle %A Lee, Kyung-min %A Koss, Brian %A Budhraja, Amit %A T. Opferman, Joseph %A Kim, Kwangho %A Arteaga, Carlos L. %A Moore, William J. %A Olejniczak, Edward T. %A Savona, Michael R. %A Fesik, Stephen W. %D 2019 %T Discovery of Potent Myeloid Cell Leukemia‑1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer %U 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 %R 10.1021/acs.jmedchem.8b01991.s002 %2 https://acs.figshare.com/ndownloader/files/14897321 %K myeloid cell leukemia %K structure-based design %K B cell lymphoma 2 family inhibitors %K Mcl -1-dependent cancers %K breast cancer xenografts %K Compound 42 %K Mcl -1-dependent tumor cell lines %K Human Cancer Overexpression %K Mouse Xenograft Models %K animal xenograft models %X 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. %I ACS Publications