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

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.