2. Academic Validation
  3. Discovery of a Myeloid Cell Leukemia 1 (Mcl-1) Inhibitor That Demonstrates Potent In Vivo Activities in Mouse Models of Hematological and Solid Tumors

Discovery of a Myeloid Cell Leukemia 1 (Mcl-1) Inhibitor That Demonstrates Potent In Vivo Activities in Mouse Models of Hematological and Solid Tumors

  • J Med Chem. 2024 Aug 22;67(16):14370-14393. doi: 10.1021/acs.jmedchem.4c01188.
James C Tarr 1,  James M Salovich 1,  Martin Aichinger 2,  KyuOk Jeon 1,  Nagarathanam Veerasamy 1,  John L Sensintaffar 1,  Heribert Arnhof 2,  Matthias Samwer 2,  Plamen P Christov 3,  Kwangho Kim 3,  Tobias Wunberg 2,  Norbert Schweifer 2,  Francesca Trapani 2,  Allison Arnold 1,  Florian Martin 2,  Bin Zhao 1,  Nagaraju Miriyala 1,  Danielle Sgubin 1,  Stuart Fogarty 1,  William J Moore 4,  Gordon M Stott 4,  Edward T Olejniczak 1,  Harald Engelhardt 2,  Dorothea Rudolph 2,  Taekyu Lee 1,  Darryl B McConnell 2,  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 Discovery Research, Boehringer Ingelheim Regional Center Vienna GmbH & Co KG, 1120 Vienna, Austria.
  • 3 Molecular Design and Synthesis Center, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37323-0146, United States.
  • 4 Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21701-4907, United States.
PMID: 39102508 DOI: 10.1021/acs.jmedchem.4c01188
Abstract

Myeloid cell leukemia 1 (Mcl-1) is a key regulator of the intrinsic Apoptosis pathway. Overexpression of Mcl-1 is correlated with high tumor grade, poor survival, and both intrinsic and acquired resistance to Cancer therapies. Herein, we disclose the structure-guided design of a small molecule Mcl-1 Inhibitor, compound 26, that binds to Mcl-1 with subnanomolar affinity, inhibits growth in Cell Culture assays, and possesses low clearance in mouse and dog pharmacokinetic (PK) experiments. Evaluation of 26 as a single agent in Mcl-1 sensitive hematological and solid tumor xenograft models resulted in regressions. Co-treatment of Mcl-1-sensitive and Mcl-1 insensitive lung Cancer derived xenografts with 26 and docetaxel or topotecan, respectively, resulted in an enhanced tumor response. These findings support the premise that pro-apoptotic priming of tumor cells by other therapies in combination with Mcl-1 inhibition may significantly expand the subset of cancers in which Mcl-1 inhibitors may prove beneficial.

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