posted on 2024-03-11, 05:08authored byJames 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. Structure-guided
optimization, including several computational methods, led to the
discovery of two structurally distinct series of SHP2 inhibitors binding
to the previously reported allosteric tunnel binding site (Tunnel
Site). One of these series was advanced to a low-nanomolar lead that
inhibited tumor growth when dosed orally to mice bearing HCC827 xenografts.
Furthermore, a third series of SHP2 inhibitors was discovered binding
to a previously unreported site, lying at the interface of the C-terminal
SH2 and catalytic domains.