New Potent Inhibitor\nof Transforming Growth Factor-Beta\n(TGFβ) Signaling that is Efficacious against Microsatellite\nStable Colorectal Cancer Metastasis in Combination with Immune Checkpoint\nTherapy in Mice

Blockade of the TGFβ signaling pathway has emerged\nfrom preclinical\nstudies as a potential treatment to enhance the efficacy of immune\ncheckpoint inhibition in advanced colorectal cancer (CRC) and several\nother types of cancer. However, clinical translation of first-generation\ninhibitors has shown little success. Here, we report the synthesis\nand characterization of HYL001, a potent inhibitor of TGFβ receptor\n1 (ALK5), that is approximately 9 times more efficacious than the\nstructurally related compound galunisertib, while maintaining a favorable\nsafety profile. HYL001 in combination with immune checkpoint blockade\n(anti-PD1) eradicates liver metastases generated in mice by microsatellite\nstable, aggressive colorectal cancer tumors at doses where galunisertib\nis ineffective.