Chemical Name : AMG-706(Motesanib)/
CAS : 453562-69-1
Synonyms: MOTESANIB DIPHOSPHATE
A multitargeted growth factor receptor kinase inhibitor to VEGFR, FGFR3, PDGFR and c-KIT. CHIR-258 was highly potent against FLT3 (1 nmol/L) with nanomolar activity against c-KIT (2 nmol/L), VEGFR1/2/3 (10 nmol/L); FGFR1/3 (8 nmol/L); PDGFRß (27 nmol/L) and CSF-1R (36 nmol/L). To confirm selectivity against class III, IV, and V RTKs, CHIR-258 was tested against other kinases in the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways and was found to have negligible activity (IC50 > 10 Amol/L). CHIR-258 potently inhibited proliferation of MV4;11 cells in a dose-dependent manner with EC50 = 13 nmol/L. Although similar concentrationdependent effects on proliferation were observed with RS4; 11 cells, they were f24-fold less sensitive to CHIR-258 (EC50 =315 nmol/L). The antiproliferative effect of CHIR-258 was also tested on the FLT3 ITD mutant cells, MOLM13 and MOLM14 with EC50 concentrations similar to those seen with MV4;11 (EC50,6 nmol/L; data not shown). These data suggest that CHIR-258 is active on both FLT3 ITD and WT leukemic cells, with the constitutively active receptor being more sensitive to inhibition.
1. In vivo target modulation and biological activity of CHIR-258, a multitargeted growth factor receptor kinase inhibitor, in colon cancer models. Lee SH, Lopes de Menezes D, Vora J, Harris A, Ye H, Nordahl L, Garrett E, Samara E, Aukerman SL, Gelb AB, Heise C. Clin Cancer Res. 2005 May 15;11(10):3633-41.
2. CHIR-258 is efficacious in a newly developed fibroblast growth factor receptor 3-expressing orthotopic multiple myeloma model in mice. Xin X, Abrams TJ, Hollenbach PW, Rendahl KG, Tang Y, Oei YA, Embry MG, Swinarski DE, Garrett EN, Pryer NK, Trudel S, Jallal B, Mendel DB, Heise CC. Clin Cancer Res. 2006 Aug 15;12(16):4908-15.