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

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

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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