Abstract 3624: A novel, selective FGFR inhibitor that causes blockade of FGFR autophosphorylation shows a broad-spectrum of anti-tumor activity in preclinical xenograft tumor models
Authors: Zhao Genshi , Li Wei-ying , Chen Daohong , Henry James R. , Bloem laura , huss karen , peng sheng-bin , mccann denis J. 
Published: February 2011

Abstract
Anti-angiogenic agents targeting VEGF/VEGFR including Bevacizumab, Sorafenib, and Sunitinib that target blood vessel formation in rapidly growing cancer cells are very effective cancer therapies in the clinic. However, these anti-angiogenic agents also have debilitating side effects, such as hypertension and bleeding, which thereby limit their use in many patients in which the anti-VEGF/VEGFR based therapies are contraindicated. Furthermore, the emergence of resistance to the anti-VEGF/VEGFR based therapies in the clinic due to over-expression of FGF2 or other growth factors could pose a serious challenge to their current use in the clinic. The FGFRs are receptor tyrosine kinases that are present in many types of tumor cells as well as endothelial cells, and play an important role in tumor cell growth, survival, and migration, and also in maintaining tumor angiogenesis. Over-expression of FGFRs or aberrant regulation of their activities has been implicated in many forms of human malignancies. Therefore, targeting FGFRs for cancer treatment represents an attractive strategy that has the potential to treat a variety of cancers by simultaneously inhibiting tumor cell growth, survival, and migration, and also tumor angiogenesis without the side effects associated with the VEGF/VEGFR based therapies. Here, we describe a selective small molecule inhibitor of FGFRs. The FGFR inhibitor is active against all four FGF receptors (IC50 = 2.6 to 7.7 nM) as revealed by biochemical autophosphorylation assays. It also exhibits a potent activity against FGFR or FGFR-mediated Erk phosphorylation in several cancer cell lines (IC50 = 0.6 to 1.5 nM). In addition, in vitro cell based assays have shown that this inhibitor is much more active at inhibiting the proliferation of FGFR-dependent than FGFR-independent cancer cell lines (IC50s = 3-2,600 nM). Furthermore, in vitro selectivity assays have established that this inhibitor exhibits a robust preferential activity in inhibiting FGF- over VEGF-mediated cord formation (IC50s = 0.6 nM for FGF and 3.6 nM for VEGF). Consistent with these in vitro selectivity data, in vivo target inhibition assays have also demonstrated that the FGFR inhibitor has a potent, yet much higher activity against FGF- than VEGF-mediated target phosphorylation in mice (TEC50s and TEC90s of 6 and 29 nM for FGFR, and 35 and 252 nM for VEGFR, respectively). Finally, the FGFR inhibitor shows an excellent broad-spectrum anti-tumor activity in xenograft tumor models representing several major cancer histologies including bladder cancer when dosed at TED50 (1.3 mg/kg) and especially at TED90 (3.2 mg/kg). Thus, the FGFR inhibitor exhibits a very well behaved PK/PD relationship. Currently, the FGFR inhibitor is being further evaluated for its potential utility in the clinic.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3624.