Src-homology-2-containing protein tyrosine phosphatase 2 (SHP2), encoded by the PTPN11 gene, is a classical nonreceptor protein tyrosine phosphatase (PTP). SHP2 is a ubiquitous protein tyrosine phosphatase with a relatively conserved structure and function. It has emerged as a key downstream regulator of several receptor tyrosine kinases (RTKs) and cytokine receptors, functioning as a positive or negative modulator in multiple signaling pathways. For example, SHP2 plays an important in cell proliferation and differentiation pathways induced by various growth factors and cytokines. Besides, as an oncogene, SHP2 regulates cancer cell survival and proliferation primarily through activation of the RAS-Erk signaling pathway, mainly dependent on its phosphatase activity.

In healthy cells, SHP2 mainly takes an autoinhibited, inactive form. And SHP2 is activated upon binding of phosphopeptides to the N-SH2 domain. On the contrary, the dysregulation of SHP2 plays an important role in the pathogenesis of many human diseases. Such as Noonan syndrome (NS), LEOPARD syndrome (LS) and multiple types of cancer, including leukemia, lung and breast cancer, liver cancer and neuroblastoma, etc. SHP2 plays diverse roles in almost all of the cancer-related processes including cancer invasion and metastasis, apoptosis, DNA damage, cell proliferation, senescence, cell cycle regulation and drug resistance.

IACS-15414 is a potent and orally active SHP2 inhibitor.

IACS-15414 is a potent and orally active SHP2 inhibitor. Importantly, IACS-15414 does not bind to the hERG channel at concentrations up to 50 μM nor does it exhibit any functional activity in the manual patch clamp assay at concentrations up to 100 μM. IACS-15414 suppresses MAPK pathway signaling in tumors in a time-dependent and dose-dependent manner. In addition, IACS-15414 shows time-dependent and dose-dependent plasma exposure after a single oral administration. Therefore, IACS-15414 exhibits significant anti-tumor efficacy in MIA PaCa-2 and KYSE-520 mouse xenograft model.

All in all, IACS-15414 is a potent and orally active SHP2 inhibitor.

[1]. Guo W, et, al. J Pharmacol Sci. 2020 Nov;144(3):139-146.