Abstract A257: Antitumor activity of E‐3810, a new, potent and selective dual inhibitor of VEGF and FGF receptors

E‐3810, 6‐[[7‐[(1‐aminocyclopropyl)methoxy]‐6‐methoxy‐4‐quinolyl]oxy]‐N‐methyl‐naphthalene‐1‐carboxamide, is a novel small molecule that potently and selectively inhibits VEGFR1‐3 and FGFR‐1 tyrosine kinases (TKs) with IC 50 in the 10‐20 nM range. Concentrations at least 1‐order higher were required to inhibit FGFR‐2 and 3, PDGFRα and β and c‐Kit receptors and no relevant activity was seen against different cancer‐related TKs. E‐3810 1‐10 nM inhibited the ligand‐dependent phosphorylation of VEGFR‐2 and FGFR‐1 and the downstream phosphorylation of Erk in HUVEC cells; inhibition of PDGFR‐ auto‐phosphorylation in NIH‐3T3 cells was detected at concentrations higher than 100 nM. E‐3810 inhibited the VEGF‐ and FGF‐driven growth of HUVEC cells (IC 50 40‐50 nM), while anti‐proliferative activity on different human cancer cell lines was shown at 10‐30 M concentrations. E‐3810 was tested in different human tumor xenografts in nude mice, including colon HT‐29, ovarian A‐2780, renal A498, RXF393 and SKN12I carcinomas. A dose dependent antitumor effect was observed in a range from 10 to 40 mg/kg given orally for 30 consecutive days. The optimal dose schedule, 20 mg/kg for 30 days, was well tolerated and caused up to 90% suppression of tumor growth. Sustained growth inhibition was also seen when treatment was repeated after a 2‐week dosing interval or when dosing was initiated at a larger tumor volume (average 400 mm 3 ). Tumor regression was observed in the RXF393 xenograft. E‐3810 showed antitumor activity equal or better than Sunitinib and Brivanib at their respective optimal doses. Pharmacokinetic studies in mice demonstrated high oral bioavailability, high volume of distribution and terminal half life of 4 hrs. After single and repeated administration E‐3810 systemic exposure was proportional to the dose, without any accumulation after repeated doses. The good bioavailability and the remarkable antitumor activity of E‐3810 in several tumor xenografts make this compound an interesting candidate for clinical development. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A257.