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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. Further, 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.

Authors:
 [1];  [2];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [3];  [1];  [4];  [4];  [1];  [5];  [5] more »;  [5];  [2];  [1];  [6];  [1];  [3]; ORCiD logo [1] « less
+ Show Author Affiliations
  1. Vanderbilt Univ. School of Medicine, Nashville, TN (United States)
  2. Vanderbilt Univ., Nashville, TN (United States)
  3. Vanderbilt-Ingram Cancer Center, Nashville, TN (United States)
  4. National Cancer Institute, Bethesda, MD (United States)
  5. St. Jude Children’s Research Hospital, Memphis, TN (United States)
  6. Frederick National Lab. for Cancer Research, MD (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH); National Cancer Institute (NCI); E. P. Evans Foundation; Biff Ruttenberg Foundation; Vanderbilt-Ingram Cancer Center; Vanderbilt Digestive Disease Research Center
OSTI Identifier:
1515302
Grant/Contract Number:  
HHSN261200800001E; P50CA098131; AC02-06CH11357; S10 RR026915
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 62; Journal Issue: 8; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; Cancer; Rodent models; Cells; Inhibitors; Screening assays

Citation Formats

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, Ramsey, Haley E., Cook, Rebecca S., Hollingshead, Melinda, Davis Millin, Myrtle, Lee, Kyung-min, Koss, Brian, Budhraja, Amit, Opferman, Joseph T., Kim, Kwangho, Arteaga, Carlos L., Moore, William J., Olejniczak, Edward T., Savona, Michael R., and 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. United States: N. p., 2019. Web. doi:10.1021/acs.jmedchem.8b01991.
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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, Ramsey, Haley E., Cook, Rebecca S., Hollingshead, Melinda, Davis Millin, Myrtle, Lee, Kyung-min, Koss, Brian, Budhraja, Amit, Opferman, Joseph T., 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. United States. https://doi.org/10.1021/acs.jmedchem.8b01991
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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, Ramsey, Haley E., Cook, Rebecca S., Hollingshead, Melinda, Davis Millin, Myrtle, Lee, Kyung-min, Koss, Brian, Budhraja, Amit, Opferman, Joseph T., Kim, Kwangho, Arteaga, Carlos L., Moore, William J., Olejniczak, Edward T., Savona, Michael R., and Fesik, Stephen W. Sat . "Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer". United States. https://doi.org/10.1021/acs.jmedchem.8b01991. https://www.osti.gov/servlets/purl/1515302.
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@article{osti_1515302,
title = {Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer},
author = {Lee, Taekyu and Christov, Plamen P. and Shaw, Subrata and Tarr, James C. and Zhao, Bin and Veerasamy, Nagarathanam and Jeon, Kyu Ok and Mills, Jonathan J. and Bian, Zhiguo and Sensintaffar, John L. and Arnold, Allison L. and Fogarty, Stuart A. and Perry, Evan and Ramsey, Haley E. and Cook, Rebecca S. and Hollingshead, Melinda and Davis Millin, Myrtle and Lee, Kyung-min and Koss, Brian and Budhraja, Amit and Opferman, Joseph T. and Kim, Kwangho and Arteaga, Carlos L. and Moore, William J. and Olejniczak, Edward T. and Savona, Michael R. and Fesik, Stephen W.},
abstractNote = {Overexpression of myeloid cell leukemia-1 (Mcl-1) in cancers correlates with high tumor grade and poor survival. Further, 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.},
doi = {10.1021/acs.jmedchem.8b01991},
journal = {Journal of Medicinal Chemistry},
number = 8,
volume = 62,
place = {United States},
year = {Sat Mar 30 00:00:00 EDT 2019},
month = {Sat Mar 30 00:00:00 EDT 2019}
}
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Journal Article:
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Publisher's Version of Record
https://doi.org/10.1021/acs.jmedchem.8b01991
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    Works referencing / citing this record:

    MCL-1 inhibitors – where are we now (2019)?
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    Therapeutic inhibition of Mcl-1 blocks cell survival in estrogen receptor-positive breast cancers
    journal, September 2019

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