Alofanib, An Allosteric Inhibitor of FGFR2
Posted On 2019-03-28
FGF family participates in a variety of physiological processes in adult organism including regulation of angiogenesis. FGF acts via high affinity binding to specific receptors (FGFR) in various cells and stimulates cell proliferation, differentiation, and migration. Angiogenesis plays a pivotal role in the development of various physiological and pathological processes. Therefore, inhibition of tumor angiogenesis is a highly effective approach in anti-tumor therapy. Alofanib is a low-molecular allosteric inhibitor of FGFR2. Preclinical studies of Alofanib show pronounced antitumor activity of this substance.
Firstly, Alofanib binds to the extracellular FGFR2 receptor domain beyond its active center and modulating the receptor conformation. It inhibits phosphorylation of FRS2α with IC50s of 7 and 9 nM in cancer cells expressing different FGFR2 isoforms. Additionally, in a panel of four cell lines representing several tumour types, it inhibited FGF-mediated proliferation with GI50s of 16-370 nM. Alofanib dose dependently inhibited the proliferation and migration of human and mouse endothelial cells compared with brivanib and bevacizumab.
Secondly, treatment with Alofanib also ablated experimental FGF-induced angiogenesis in vivo. In a FGFR-driven human tumour xenograft model, oral administration of Alofanib showed good tolerance and resulted in potent antitumour activity. Importantly, it was effective in FGFR2-expressing models. Preclinical studies demonstrated that expression or amplification of FGFR2 on tumor cells is an important predictor of the efficiency of Alofanib therapy. The higher FGFR2 expression is, the more active the substance is.
To conclude, Alofanib is a potent FGFR2 inhibitor and provides strong rationale for its evaluation in patients with FGFR2-driven cancers.