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
  • 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.
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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