RPI-1 is an ATP-dependent Ret tyrosine kinase and inhibitor [1]. RPI-1 also inhibits c-Met activation and expression [2].
The ret proto-oncogene encodes a receptor protein tyrosine kinase involved in the etiology of human tumors. RET loss of function mutations are associated with the development of Hirschsprung's disease, and gain of function mutations are associated with the development of various types of human cancer, including medullary thyroid carcinoma, multiple endocrine neoplasias, pheochromocytoma and parathyroid hyperplasia.
In NIH3T3 fibroblasts expressing the Ret/ptc1 target tyrosine kinase (NIH3T3ptc1), RPI-1 preferentially inhibited the anchorage-independent growth with IC50 value of 0.97 μM [1]. In the N592 SCLC and H460 NSCLC cell lines, RPI-1 dose-dependently inhibited Met phosphorylation. In H460 cells, RPI-1 also inhibited HGF-induced Met tyrosine phosphorylation in a dose-dependent way [2].
In mice implanted s.c. with H460 cells, RPI-1 with 100 and 150 mg/kg significantly reduced the mean number of macroscopic lung metastases by 57% and 75%, respectively. In primary s.c. growing H460 tumors, RPI-1 exhibited significant antiangiogenic effect [2].
References:
[1]. Lanzi C, Cassinelli G, Pensa T, et al. Inhibition of transforming activity of the ret/ptc1 oncoprotein by a 2-indolinone derivative. Int J Cancer. 2000 Feb 1;85(3):384-90.
[2]. Cassinelli G, Lanzi C, Petrangolini G, et al. Inhibition of c-Met and prevention of spontaneous metastatic spreading by the 2-indolinone RPI-1. Mol Cancer Ther. 2006 Sep;5(9):2388-97.