SHP2 is a ubiquitously expressed protein tyrosine phosphatase required for growth factor signalling downstream of receptor tyrosine kinases (RTKs) and plays a role in regulating many cellular processes.
Genetic knockdown and pharmacological inhibition of SHP2 inhibits proliferation of RTK-driven cancer cell lines and suppresses RAS/MAPK signalling.
SHP2 inhibitors are a promising therapeutic approach as RTK deregulation often leads to a wide range of cancers and several compounds are being tested in the clinic.
Using our fragment-based screening approach, PyramidTM, we identified fragment hits binding to the tunnel region<sup>1</sup> between the phosphatase domain and the C-SH2 domain of SHP2 which were improved using structure-guided design.
Here we describe the optimisation of mM fragment hits into potent SHP2 antagonists with in vitro and in vivo anti-tumour activity.