9J9D

Crystal structure of ALK5 kinase domain in complex with inhibitor HM-279

This is a non-PDB format compatible entry.

Summary for 9J9D

• Entry DOI: 10.2210/pdb9j9d/pdb
• Descriptor: TGF-beta receptor type-1, 2-((1-(but-2-yn-1-yl)-1H-pyrazol-4-yl)(cyclopropylmethyl)amino)-5-(4-(dimethylcarbamoyl)-1H-pyrrol-2-yl)thiazole-4-carboxamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: protein kinase, inhibitor complex, oncoprotein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 35653.04

Authors

Arai, M.,Hanada, M.,Taniguchi, H.,Ohmoto, H.,Naka, K.,Sawa, M. (deposition date: 2024-08-22, release date: 2025-04-02, Last modification date: 2025-04-23)

Primary citation

Arai, M.,Hanada, M.,Taniguchi, H.,Nakajima, F.,Ohmoto, H.,Inoue, T.,Naka, K.,Sawa, M.
Discovery of HM-279, a Potent Inhibitor of ALK5 for Improving Therapeutic Efficacy of Cancer Immunotherapy.
J.Med.Chem., 68:7106-7118, 2025

PubMed 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 , focusing on improving off-target selectivity. Compound (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.

PubMed: 40108955
DOI: 10.1021/acs.jmedchem.4c02293

Experimental method

X-RAY DIFFRACTION (1.337 Å)