Discovery of novel phenyl urea SHP2 inhibitors with anti-colon cancer and potential immunomodulatory effects

Abstract

Src Homology-2 Domain Containing Protein Tyrosine Phosphatase-2 (SHP2) is a non-receptor-type protein tyrosine phosphatase (PTP), which is recognized as potential and attractive cancer therapeutic target. Currently, no SHP2 inhibitors have been approved for clinical use, and colorectal cancer (CRC) cells exhibited frequent resistance to reported SHP2 inhibitors, such as SHP099 and TNO155. Herein, we reported our discovery and optimization of phenyl urea as novel SHP2 inhibitors. A8, the most potential SHP2 inhibitor, exhibited great antiproliferative activities against SHP099/TNO155-insensitive tumor cell lines, and rescued PD-L1-mediated immunosuppression. A8 significantly suppressed in vivo tumor growth in a CT26 mouse model and activated immunomodulatory effects in tumor microenvironment. Our work demonstrated that A8 has the potential to be a lead compound for the further development of SHP2 inhibitor and the treatment of CRC.