TY - JOUR
T1 - New Potent Inhibitor of Transforming Growth Factor-Beta (TGFβ) Signaling that is Efficacious against Microsatellite Stable Colorectal Cancer Metastasis in Combination with Immune Checkpoint Therapy in Mice
AU - Tauriello, Daniele V. F.
AU - Sancho, Elena
AU - Byrom, Daniel
AU - Sanchez-Zarzalejo, Carolina
AU - Salvany, Maria
AU - Henriques, Ana
AU - Palomo-Ponce, Sergio
AU - Sevillano, Marta
AU - Hernando-Momblona, Xavier
AU - Matarin, Joan A.
AU - Ramos, Israel
AU - Ruano, Irene
AU - Prats, Neus
AU - Batlle, Eduard
AU - Riera, Antoni
N1 - Publisher Copyright:
© 2024 The Authors. Published by American Chemical Society.
PY - 2024/10/1
Y1 - 2024/10/1
N2 - Blockade of the TGFβ signaling 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 shown 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 favorable safety profile. HYL001 in combination with immune checkpoint blockade (anti-PD1) eradicates liver metastases generated in mice by microsatellite stable, aggressive colorectal cancer tumors at doses where galunisertib is ineffective.
AB - Blockade of the TGFβ signaling 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 shown 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 favorable safety profile. HYL001 in combination with immune checkpoint blockade (anti-PD1) eradicates liver metastases generated in mice by microsatellite stable, aggressive colorectal cancer tumors at doses where galunisertib is ineffective.
UR - http://www.scopus.com/inward/record.url?scp=85205785660&partnerID=8YFLogxK
U2 - 10.1021/acsptsci.4c00374
DO - 10.1021/acsptsci.4c00374
M3 - Article
C2 - 39816803
SN - 2575-9108
VL - 8
SP - 97
EP - 112
JO - ACS Pharmacology & Translational Science
JF - ACS Pharmacology & Translational Science
IS - 1
ER -
