XL184 (Cabozantinib) is an oral, small-molecule inhibitor, which has potent activity toward VEGFR2 (IC50=0.035nM) and MET (IC50 = 1.3nM), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3 [1].

Multiple receptor tyrosine kinases (RTKs) are sometimes activated in the same tumor. Inhibition of single RTK may lead to compensatory signaling that maintains cell growth. Targeting multiple kinases simultaneously might overcome both intrinsic and acquired resistance to antitumor drugs. XL184 has been shown to inhibit phosphorylation of MET and VEGFR2, to disrupt angiogenesis and cellular migration and invasion, and to promote tumor and endothelia cell death1. Inhibition of c-Met with XL184 blocks self-renewal capacity in pancreatic cancer stem cells (CSCs) [2]. In mouse models and preclinical studies, XL184 demonstrates robust antiangiogenic, antitumor, and anti-invasive effects, dramatically alters tumor pathology, prevents the development of metastases, and reduces tumor burden [1-3].