HYL001, a new potent TGFβ signaling inhibitor that is efficacious against microsatellite stable CRC metastasis in combination with immune checkpoint therapy in mice

Blockade of the TGFβ signalling pathway has emerged from preclinical studies as a potential treatment to enhance the efficacy of immune checkpoint inhibition in advanced colorectal cancer (CRC) and several other types of cancer. However, clinical translation of first-generation inhibitors has known little success. Here, we report the synthesis and characterization of HYL001, a potent inhibitor of TGFβ receptor 1 (ALK5), that is approximately 9 times more efficacious than the structurally related compound galunisertib, while maintaining a favourable safety profile. HYL001 in combination with immune checkpoint blockade (anti-PD1) eradicates liver metastases generated in mice by microsatellite stable, aggressive colorectal cancer tumours at doses where galunisertib is ineffective. ![Figure][1] ### Competing Interest Statement DT, DB, JM, AR, and EB hold a patent on the synthesis and use of HYL001. E.B. is author in a patent describing bispecific antibodies to target cancer stem cells. The laboratory of E.B. has received research funding from MERUS and INCYTE. E.B. has received honoraria for consulting from Genentech. [1]: pending:yes