Discovery of HM-279, a Potent Inhibitor of ALK5 for Improving Therapeutic Efficacy of Cancer Immunotherapy

  • J Med Chem. 2025 Apr 10;68(7):7106-7118. doi: 10.1021/acs.jmedchem.4c02293.
Mai Arai  1 ,  Mitsuharu Hanada  1 ,  Haruka Taniguchi  1 ,  Fumio Nakajima  1 ,  Hiroshi Ohmoto  1 ,  Tsuyoshi Inoue  2 ,  Kazuhito Naka  3 ,  Masaaki Sawa  1
Affiliations
  • 1. Research and Development, Carna Biosciences, Inc., BMA 3F, 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
  • 2. Graduate School of Pharmaceutical Sciences, Osaka University, Yamada-oka 1-6, Suita, Osaka 565-0871, Japan.
  • 3. Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
PMID: 40108955 DOI: 10.1021/acs.jmedchem.4c02293
Abstract

Activin receptor-like kinase 5 (ALK5) is a type I receptor serine/threonine kinase and responsible for the TGF-β signaling pathway. ALK5 is thought to be a key player in the tumor microenvironment to promote tumor progression by affecting the Anticancer immunity. Therefore, ALK5 is an attractive drug target for modulating TGF-β signaling pathways to improve the therapeutic efficacy of Cancer Immunotherapy. We report the optimization of a series of thiazole analogues starting from lead compound 6, focusing on improving off-target selectivity. Compound 19f (HM-279) was identified as a potent ALK5 Inhibitor with an acceptable off-target selectivity and favorable ADME/PK properties. Oral administration of HM-279 demonstrated antitumor activity in a CT26.WT colon carcinoma syngeneic mouse model as a single agent and in combination with the anti-PD-1 antibody through CD8+ T cell immunity.

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