Receptor d’origin nantais (RON) is a receptor tyrosine kinase (RTK), which is usually expressed at a low level in epithelial cells. In terms of source and function, it is closely related to c-Met. Specifically, both RON and c-Met respond to their respective ligands: macrophage stimulating protein (MSP) of RON and hepatocyte growth factor (HGF) of c-Met. Besides, RON and c-Met initiate these functions through unique docking sites at their COOH ends. Moreover, C-met and RON can be constitutively activated by the ligand-independent mechanisms in tumor cells. Furthermore, constitutive activation of c-met may come from gene amplification or activation mutation. Meanwhile, C-met receptor tyrosine kinase plays an important role in cell survival, proliferation, differentiation, and tumorigenesis, especially in metastasis. Therefore, there are efforts to develop effective small chemical inhibitors of c-Met receptor kinase. SYN1143 is a potent and selective dual inhibitor of c-Met/RON.
SYN1143 is a potent and selective dual inhibitor of c-Met/RON.
How does SYN1143 work on the target? Let’s study it together. In the beginning, SYN1143 is a potent and selective dual inhibitor of c-Met/RON, with IC50s of 4 and 9 nM, respectively. Meanwhile, SYN1143 has weak inhibitory activity on Lck, Tie2, Src, and BTK with IC50s ranging from 160 to 710 nM. Meanwhile, SYN1143 has the potential for the research of cancers that RON and c-Met are activated.
Secondly, SYN1143 with 10-1000 nM of 1 h inhibits c-Met-mediated signaling and functional activity in HT-29 and BxPC3 cells. Importantly, SYN1143 inhibits RON-mediated signaling and functional activity in NIH3T3 RON and BxPC3 cells. Additionally, SYN1143 inhibits c-Met signaling and cell proliferation in MC3T3-E1 and C3H10T1/2 cells. In particular, SYN1143 potentiates osteogenic differentiation of precursor cells.
Last but not the least, SYN1143 with 10-100 mg/kg of p.o. for 22 days inhibits the growth of c-Met-dependent and constitutively active RON-expressing tumors in mice. At the same time, SYN1143 stimulates bone formation in critical-sized defects of mouse calvarial bone.
All in all, SYN1143 is a potent and selective dual inhibitor of c-Met/RON.
References:
Zhang Y, et, al. Cancer Res. 2008 Aug 15;68(16):6680-7.