James E H Day, Valerio Berdini, Joan Castro, Gianni Chessari, Thomas G Davies, Philip J Day, Jeffrey D St Denis, Hideto Fujiwara, Satoshi Fukaya, Christopher C F Hamlett, Keisha Hearn, Steven D Hiscock, Rhian S Holvey, Satoru Ito, Navrohit Kandola, Yasuo Kodama, John W Liebeschuetz, Vanessa Martins, Kenichi Matsuo, Paul N Mortenson, Sandra Muench, Yoko Nakatsuru, Hiroaki Ochiiwa, Nicholas Palmer, Torren Peakman, Amanda Price, Michael Reader, David C Rees, Sharna J Rich, Alpesh Shah, Yoshihiro Shibata, Tomoko Smyth, David G Twigg, Nicola G Wallis, Glyn Williams, Nicola E Wilsher, Andrew Woodhead, Tadashi Shimamura, Christopher N Johnson
The ubiquitously expressed protein tyrosine phosphatase SHP2 is required for signaling downstream of receptor tyrosine kinases (RTKs) and plays a role in regulating many cellular processes. Genetic knockdown and pharmacological inhibition of SHP2 suppresses RAS/MAPK signaling and inhibit the proliferation of RTK-driven cancer cell lines. Here, we describe the first reported fragment-to-lead campaign against SHP2, where X-ray crystallography and biophysical techniques were used to identify fragments binding to multiple sites on SHP2...
March 10, 2024: Journal of Medicinal Chemistry