| XL184 is a potent inhibitor of RTKs, including MET, VEGFR2, and RET. XL184 inhibits MET and VEGFR2 with IC50 values of 1.3 and 0.035 nM, respectively. Besides, XL184 inhibits MET-activating kinase domain mutations Y1248H, D1246N, or K1262R with IC50 of 3.8, 11.8, and 14.6 nM, respectively. XL184 also displays strong inhibition of several kinases that have been implicated in tumor pathobiology, including KIT, RET, AXL, TIE2, and FLT3 with IC50 of 4.6, 5.2, 7, 14.3, and 11.3 nM, respectively. In cellular assays, XL184 inhibits phosphorylation of MET and VEGFR2, as well as KIT, FLT3, and AXL with IC50 values of 7.8, 1.9, 5.0, 7.5, and 42 µM, respectively. XL184 inhibits tubule formation in response to conditioned media derived from cultures of MDA-MB-231, A431, HT1080, B16F10 cells with IC50s of 5.1, 4.1, 7.7, 4.7 nM. Meanwhile, XL-184 potently inhibits HGF-induced migration with IC50 of 31 nM and invasion of B16F10 cells with IC50 of 9 nM.[1] XL184 exhibits significant antiangiogenic and antitumor activity in a broad range of tumor models, including a model of medullary thyroid cancer (MTC) with an activating RET mutation. Treatment with XL184 results in decreased tumor invasiveness and decreased metastasis compared with either vehicle control or agents targeting VEGF signaling without MET inhibition. [2] XL184 blocks phosphorylation of c-Met and VEGFR at nanomolar or subnanomolar concentrations to assess the interaction of these receptors in tumors. Treatment with XL184 eliminates approximately 80% of the tumor vasculature, reduces pericytes and empty basement membrane sleeves, causes widespread intratumoral hypoxia and tumor cell apoptosis, and slows regrowth of the tumor vasculature after drug withdrawal. Importantly, XL184 also decreases invasiveness of primary tumors and reduced metastasis. [3] In vivo, in HCC827GC6 xenograft tumors established in female nude mice, single-agent XL184 (10 mg/kg p.o., single dose) elicits slightly greater inhibition of tumor growth than that of single-agent erlotinib (100 mg/kg p.o., single dose). XL184 inhibits MET phosphorylation and is associated with a dose-dependent regression of xenograft tumors. [4] |
