@article{2a888c57722d466d9e66d1b271b140a8,
title = "Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer",
abstract = "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.",
author = "Taekyu Lee and Christov, {Plamen P.} and Subrata Shaw and Tarr, {James C.} and Bin Zhao and Nagarathanam Veerasamy and Jeon, {Kyu Ok} and Mills, {Jonathan J.} and Zhiguo Bian and Sensintaffar, {John L.} and Arnold, {Allison L.} and Fogarty, {Stuart A.} and Evan Perry and Ramsey, {Haley E.} and Cook, {Rebecca S.} and Melinda Hollingshead and {Davis Millin}, Myrtle and Lee, {Kyung Min} and Brian Koss and Amit Budhraja and Opferman, {Joseph T.} and Kwangho Kim and Arteaga, {Carlos L.} and Moore, {William J.} and Olejniczak, {Edward T.} and Savona, {Michael R.} and Fesik, {Stephen W.}",
note = "Funding Information: The authors thank co-workers at the High-Throughput Screening Core facility of Vanderbilt University, TN, for compound management. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Chemical Biology Consortium Contract No. HHSN261200800001E. The content of this publication does neither necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government and a career development award to S.W.F. from a NCI SPORE grant in breast cancer (Grant P50CA098131) to C.L.A. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. A portion of the experiments described here used the Vanderbilt PacVan biomolecular robotic crystallization facility, which was supported by National Institutes of Health Grant S10 RR026915. E. P. Evans Foundation Discovery Research Grant, the Adventure Allie Discovery Research Grant, and the Biff Ruttenberg Foundation to M.R.S. The Vanderbilt-Ingram Cancer Center is supported by a NIH P30 CA068485-19. Authors acknowledge the Vanderbilt-Ingram Cancer Center Hematopoietic Malignancies Tissue Repository. Flow cytometry experiments were performed in the VMC Flow Cytometry Shared Resource. The VMC Flow Cytometry Shared Resource is supported by the Vanderbilt-Ingram Cancer Center (P30 CA68485) and the Vanderbilt Digestive Disease Research Center (DK058404). Funding Information: The authors thank co-workers at the High-Throughput Screening Core facility of Vanderbilt University, TN, for compound management. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Chemical Biology Consortium Contract No. HHSN261200800001E. The content of this publication does neither necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government and a career development award to S.W.F. from a NCI SPORE grant in breast cancer (Grant P50CA098131) to C.L.A. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02- 06CH11357. A portion of the experiments described here used the Vanderbilt PacVan biomolecular robotic crystallization facility, which was supported by National Institutes of Health Grant S10 RR026915. E. P. Evans Foundation Discovery Research Grant, the Adventure Allie Discovery Research Grant, and the Biff Ruttenberg Foundation to M.R.S. The Vanderbilt-Ingram Cancer Center is supported by a NIH P30 CA068485-19. Authors acknowledge the Vanderbilt- Ingram Cancer Center Hematopoietic Malignancies Tissue Repository. Flow cytometry experiments were performed in the VMC Flow Cytometry Shared Resource. The VMC Flow Cytometry Shared Resource is supported by the Vanderbilt- Ingram Cancer Center (P30 CA68485) and the Vanderbilt Digestive Disease Research Center (DK058404). Funding Information: ●University of Wisconsin, Madison, Wisconsin 53706, United States (S.A.F.). Notes The authors declare the following competing financial interest(s): M. R. Savona receives research funding from Astex, Boehringer Ingelheim, Celgene, Incyte, Millennium, Sunesis, and TG Therapeutics, is a consultant/advisory board member for Celgene, Incyte, and Karyopharm, and has equity in Karyopharm. S. W. Fesik receives research funding from Boehringer Ingelheim. Publisher Copyright: {\textcopyright} 2019 American Chemical Society.",
year = "2019",
month = apr,
day = "25",
doi = "10.1021/acs.jmedchem.8b01991",
language = "English (US)",
volume = "62",
pages = "3971--3988",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "8",
}