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
  • 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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