SHP394 is an Orally Active and Selective Inhibitor of SHP2
Posted On 2021-05-08
SH2 containing protein tyrosine phosphatase-2 (SHP2) is an oncogenic phosphatase. SHP2 facilitates growth and survival signaling downstream of numerous receptor inputs. In addition, higher levels of SHP2 phosphorylation associate with decreased survival of breast cancer patients. Especially, SHP394 is an orally active and selective inhibitor of SHP2.
Pharmacological inhibition of SHP2 activity blocks ERK1/2 and AKT signaling. Engagement of the extracellular matrix via focal adhesion kinase also phosphorylates SHP2. Besides, SHP2 may also play a role in the PD-L1/PD-1 pathway, suggesting the applications of SHP2 inhibition in immuno-oncology. Small molecule inhibition of SHP2 has attracted significant attention in the scientific community. Overall, SHP2 constitutes a shared signaling node allowing metastatic breast cancer cells to simultaneously engage a diversity of growth and survival pathways. In addition, inhibition of SHP2 in combination with FGFR-targeted kinase inhibitors synergistically blocks the growth of metastatic breast cancer cells.
In this study, researchers described the identification of SHP394. SHP394 is an orally efficacious inhibitor of SHP2, with high lipophilic efficiency, improved potency, and enhanced pharmacokinetic properties. Protein tyrosine phosphatase SHP2 is an oncoprotein. In vivo blockade of SHP2 in the adjuvant setting decreases pulmonary metastasis and extends the survival of systemic tumor-bearing mice. SHP394 (20, 40, and 80 mg/kg BID) demonstrates a clear dose-dependent reduction in tumor volume. Moreover, SHP394 (80 mg/kg; oral gavage; twice daily) causes tumor 34% regression and reduces mouse host bodyweight.
All in all, Shp2 is an SH2-containing protein-tyrosine phosphatase. In particular, Shp2 positively regulates receptor tyrosine kinase signaling by dephosphorylating and inactivating the inhibitor. SHP394 is an orally active, selective, and allosteric inhibitor of SHP2, with a low nM IC50 value.
Sarver P, et al. 6-Amino-3-methylpyrimidinones as Potent, Selective, and Orally Efficacious SHP2 Inhibitors. J Med Chem. 2019 Feb 28;62(4):1793-1802.