Ying Kong, Xinyue Zhao, Zhaofu Wang, Siqi Yuan, Sheng Chen, Shidi Lou, Shichao Ma, Yunfeng Li, Xinghao Wang, Yangfeng Ge, Guobin Li, Hongbing Yang, Mengxi Zhao, Dandan Li, Hailong Zhang, Wenfu Tan, Juan Wang
The aberrant activation of fibroblast growth factor receptor (FGFR) acts as a potent driver of multiple types of human cancers. Despite the development of several conventional small-molecular FGFR inhibitors, their clinical efficacy is largely compromised due to low selectivity and side effects. Here, we report the selective FGFR1/2-targeting proteolysis targeting chimeric (PROTAC), BR-cpd7 that displays significant isoform specificity to FGFR1/2 with DC50 values around 10 nM, while sparing FGFR3. The following mechanistic investigation reveals the reduced FGFR signaling, through which BR-cpd7 induces cell cycle arrest and consequently blocks the proliferation of multiple FGFR1/2-dependent tumor cells...
April 22, 2024: Molecular Cancer Therapeutics