The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases (RTKs) comprises four members (FGFR1, FGFR2, FGFR3, and FGFR4) that share significant sequence homology. This family of RTKs serves as high-affinity receptors for the fibroblast growth factors (FGFs) that control cell proliferation, apoptosis, and differentiation and are involved in both developmental and adult tissue homeostasis.
Diverse researches have evaluated the important role of the FGFR family in cancer study. For instance, in multiple myeloma, recurrent chromosomal translocations of 14q32 into the immunoglobulin heavy chain switch region result in deregulated overexpression of FGFR3. Additionally, Gene amplification and protein overexpression have been reported for FGFR1, FGFR2, and FGFR4 in breast cancer.
Infigratinib (BGJ-398; NVP-BGJ398) stands for a potent inhibitor of the FGFR family. It exhibits IC50s of 0.9 nM, 1.4 nM, 1 nM, and 60 nM for FGFR1, FGFR2, FGFR3, and FGFR4, respectively.
Especially, in vitro, Infigratinib (BGJ-398) inhibits the proliferation of the FGFR1-, FGFR2-, and FGFR3-dependent BaF3 cells with IC50 values which are in the low nanomolar range.
Moreover, in vivo, Infigratinib (BGJ-398) treats orally by gavage as a suspension in PEG300/D5W (2:1, v/v) at a 20 mg/kg dose for athymic nude mice. The relevant pharmacokinetic (PK) parameters indicate that the oral bioavailability of Infigratinib (BGJ-398) in this study is 32%. What’s more, Infigratinib (BGJ-398) shows a rapid distribution from the vascular compartment into the peripheral tissues. The plasma clearance is high at 3.3 L/h/kg (61% of liver blood flow).
Infigratinib (BGJ-398) (30 mg/kg) significantly inhibits the growth of FGFR2-mutated endometrial cancer xenograft models.
References
[1]. J Med Chem. 2011 Oct 27;54(20):7066-83.
[2]. Mol Cancer Ther. 2013 May;12(5):632-42.