2. Academic Validation
  3. Discovery of Macrocyclic Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors that Demonstrate Potent Cellular Efficacy and In Vivo Activity in a Mouse Solid Tumor Xenograft Model

Discovery of Macrocyclic Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors that Demonstrate Potent Cellular Efficacy and In Vivo Activity in a Mouse Solid Tumor Xenograft Model

  • J Med Chem. 2025 Sep 11;68(17):18553-18578. doi: 10.1021/acs.jmedchem.5c01376.
James C Tarr 1,  Kyuok Jeon 1,  Nagarathanam Veerasamy 1,  Martin Aichinger 2,  James M Salovich 1,  Bin Zhao 1,  John L Sensintaffar 1,  Heribert Arnhof 2,  Tobias Wunberg 2,  Danielle Sgubin 1,  Allison Arnold 1,  Rakesh H Vekariya 1,  Plamen P Christov 3,  Kwangho Kim 3,  Julian Emanuel Fuchs 2,  Pol Karier 4,  Bodo Betzemeier 4,  Mayme Van Meveren 1,  Nagaraju Miriyala 1,  Edward T Olejniczak 1,  Harald Engelhardt 2,  Taekyu Lee 1,  Darryl 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, Vienna 1120, Austria.
  • 3 Molecular Design and Synthesis Center, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37323-0146, United States.
  • 4 Chemical Development Germany, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, Biberach an der Riß 88397, Germany.
PMID: 40864607 DOI: 10.1021/acs.jmedchem.5c01376
Abstract

The B cell lymphoma 2 (Bcl-2) family of proteins are key regulators of intrinsic Apoptosis. The antiapoptotic protein myeloid cell leukemia 1 (Mcl-1), which is associated with high tumor grade, poor survival, and resistance to treatment, has emerged as a promising candidate for treating hematological and solid cancers. Herein, we report the structure-guided design of small molecule macrocyclic Mcl-1 inhibitors based on the (R)-methyl-dihydropyrazinoindolone scaffold our group has previously disclosed. The macrocyclic inhibitors bind Mcl-1 with subnanomolar affinity and offer improved potency in Cell Culture growth inhibition assays. Inhibitor 13 achieved tumor regression in a lung cancer-derived tumor xenograft model in mice as a monotherapy. The improved potency of the macrocyclic series allowed replacement of heretofore conserved indole carboxylic acid moiety, resulting in neutral inhibitors. Amide inhibitor 25 displayed a >10-fold increase in oral bioavailability as compared to acid-containing macrocyclic or acyclic inhibitors.

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