Uses
GNF 5837 is a potent pan-Trk inhibitor which has selectivity for tropomyosin-receptor-kinase (Trk).
Biological Activity
gnf-5837 is reported to selectively suppress pan-trk potently in an oral-bioavailable manner. neurotrophins and their receptors (trks) are important in malignant transformations, chemotaxis, metastasis, and survival signaling and may contribute to the pathogenesis of a variety of tumors. the trk-inhibiting properties of gnf-5837 therefore make it a useful tool to investigate trk biology in cancer and other non-oncology indications. [1]
Biochem/physiol Actions
GNF-5837 is an orally bioavailable Trk inhibitor (IC50 = 8 and 12 nM for TrkA and TrkB, respectively). GNF-5837 inhibits growth of Ba/F3 cells expressing Tel-Trl fusions. IC50 values for growth inhibition are Tel-TrkA = 11 nM, Tel-TrkB = 9 nM and Tel-TrkC = 7 nM.
in vitro
the anti-trka activity of gnf-5837 was detected in ba/f3 and rie cells expressing both trka and ngf. in ba/f3 cells, this compound exhibited intensively anti-proliferation activity with an ic50 of 0.042 μm. rie cells expressing trka and ngf could only survive under low attachment condition and were resistant to detachment-induced apoptosis. gnf-5837 seemed to suppress cell growth and proliferation of rie cells intensively with an ic50 of 0.017 μm. moreover, gnf-5837 is reported to show inhibitory effects on c-kit and pdgfr in mo7e cells and rat-a10 cells, respectively. [1]
in vivo
mice models with tumor xenografts derived from rie cells expressing both trka and ngf were established in one study. gnf-5837 was then administered at ascending doses once daily to these mice for 10 days, with the aim to investigate the in vivo efficacy of gnf-5837. 72 and 100% tumor inhibition was reported at the dose of 50 and 100 mg/kg, respectively. at 25 mg/kg, only partial tumor growth inhibition was observed. [1]
IC 50
a potent and selective pan-trk inhibitor, suppressing the activity of trka and trkb with ic50 of 8 and 12 nm, respectively.
References
[1] albaugh f, fan y, mi y, sun fx, adrian f, li nx, jia y, sarkisova y, kreusch a, hood t, lu m, liu gx, huang sl, liu zs, loren j, tuntland t, karanewsky ds, seidel hm and molteni v. discovery of gnf-5837, a selective trk inhibitor with efficacy in rodent cancer tumor models. acs med. chem. lett. 2012. 3: 1405.
