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

  • J Med Chem. 2019 Apr 25;62(8):3971-3988. doi: 10.1021/acs.jmedchem.8b01991.
Taekyu Lee  1 ,  Plamen P Christov  2 ,  Subrata Shaw  1 ,  James C Tarr  1 ,  Bin Zhao  1 ,  Nagarathanam Veerasamy  1 ,  Kyu Ok Jeon  1 ,  Jonathan J Mills  1 ,  Zhiguo Bian  1 ,  John L Sensintaffar  1 ,  Allison L Arnold  1 ,  Stuart A Fogarty  1 ,  Evan Perry  1 ,  Haley E Ramsey  3 ,  Rebecca S Cook  4 ,  Melinda Hollingshead  5 ,  Myrtle Davis Millin  5 ,  Kyung-Min Lee  6 ,  Brian Koss  7 ,  Amit Budhraja  7 ,  Joseph T Opferman  7 ,  Kwangho Kim  2 ,  Carlos L Arteaga  6 ,  William J Moore  8 ,  Edward T Olejniczak  1 ,  Michael R Savona  3 ,  Stephen W Fesik  1
Affiliations
  • 1. Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States.
  • 2. Chemical Synthesis Core, Vanderbilt Institute of Chemical Biology , Vanderbilt University , Nashville , Tennessee 37232 , United States.
  • 3. Department of Medicine , Vanderbilt-Ingram Cancer Center , Nashville , Tennessee 37232 , United States.
  • 4. Department of Cell and Developmental Biology , Vanderbilt University School of Medicine , Nashville , Tennessee 37232 , United States.
  • 5. National Cancer Institute , Bethesda , Maryland 20892 , United States.
  • 6. Department of Hematology and Oncology , Vanderbilt University School of Medicine , Nashville , Tennessee 37232 , United States.
  • 7. Department of Cell and Molecular Biology , St. Jude Children's Research Hospital , Memphis , Tennessee 38105 , United States.
  • 8. Leidos Biomedical Research , Frederick National Laboratory for Cancer Research , Frederick , Maryland 21701 , United States.
PMID: 30929420 DOI: 10.1021/acs.jmedchem.8b01991
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.

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