| Cabozantinib, also known as XL184, is an orally bioavailable novel tysosine kinase inhibitor of c-MET and VEGF receptor 2 (VEGFR2). It inhibited MET and VEGFR2 with IC50 values of 1.3 nM and 35 pM, respectively. It also inhibited MET-activating kinase domain mutations Y1248H, D1246N, or K1262R with IC50 values of 3.8, 11.8, and 14.6 nM, respectively. It strongly inhibited several kinases that are implicated in tumor pathobiology including KIT, RET, AXL, TIE2, and FLT3 with IC50 values of 4.6, 5.2, 7, 14.3, and 11.3 nM, respectively. In cellular assays, cabozantinib inhibited phosphorylation of MET, VEGFR2, KIT, FLT3, and AXL with IC50 values of 7.8, 1.9, 5.0, 7.5, and 42 [micro]M, respectively. Cabozantinib inhibited tumor angiogenesis, tumor growth and metastasis in cancers with dysregulated MET and VEGFR signaling. Yakes F.M., et al Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol. Cancer Ther. 10: 2298-2308 (2011). Treatment of RIP-Tag2 mice with cabozantinib eliminated approximately 80% of the vasculature of spontaneous pancreatic islet tumors over 7 days, reduced pericytes and empty basement membrane sleeves, resulted in widespread intratumoral hypoxia and tumor cell apoptosis, and delayed regrowth of the tumor vasculature after drug withdrawal. Importantly, it also inhibited invasiveness of primary tumors and reduced metastasis. You W.K., et al. VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. Cancer Res. 71: 4758-4768 (2011). Cabozantinib is active in patients with medullary thyroid cancer and has an acceptable safety profile. Kurzrock R., et al. Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J. Clin. Oncol. 29: 2660-2666 (2011). Cabozantinib 40 mg daily was associated with a high rate of bone scan response and better tolerability in patients with metastatic castration-resistant prostate cancer when compared with previously reported results for cabozantinib 100 mg daily. Lee R.J., et al. A dose-ranging study of cabozantinib in men with castration-resistant prostate cancer and bone metastases. Clin Cancer Res. 19: 3088-3094 (2013). Cabozantinib demonstrated activity in patients with metastatic melanoma in a phase 2 randomized discontinuation trial. Gordon M.S. etal. Activity of Cabozantinib (XL184) in Metastatic Melanoma: Results From a Phase 2 Randomized Discontinuation Trial (RDT). http://www.exelixis.com/sites/default/files/2012-06-02_Gordon%20Melanoma_ASCO%202012%20FINAL_poster_8531.pdf Cabozantinib was active in patients with metastatic non-small cell lung cancer (NSCLC) in a phase 2 randomized discontinuation trial. Hellerstedt B.A. et al. Activity of Cabozantinib (XL184) in Metastatic NSCLC: Results From a Phase 2 Randomized Discontinuation Trial (RDT). http://www.exelixis.com/sites/default/files/2012-06-05_Hellerstedt%20NSCLC_ASCO%202012_FINAL_poster_7514.pdf response to anthracycline therapy. Cell Cycle 11: 2747-2755 (2012). Appearance: White to off-white, cystalline powder Purity: 99% (HPLC, TLC) Melting Point: 209-211C Solubility: DMSO Method for Determining Identity: NMR (DMSO-d6) and MS Storage and Stability: May be stored at RT for short-term only. Long-term storage is recommended at -20C. For maximum recovery of product, centrifuge the original vial prior to removing the cap. |
