"目錄號: HY-15343

EpigeneticsStem Cell/WntJAK/STAT Signaling-

CEP-33779是一個新穎的，選擇性，有口服活性的JAK2抑制劑，IC50值為1.8±0.6 nM。

JAK

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生物活性

Description

CEP-33779 is a novel, selective, and orally bioavailable inhibitor ofJAK2with anIC50of 1.8±0.6 nM.

IC50& Target

IC50: 1.8±0.6 nM (JAK2)[1]

In Vitro

CEP-33779, at nontoxic concentrations, significantly sensitizes overexpression of P-glycoprotein overexpressing multidrug resistance cells to its anticancer substrates. CEP-33779 significantly increases intracellular accumulation and decreases the efflux of doxorubicin by inhibiting the overexpression of P-glycoprotein transport function[3].

In Vivo

CEP-33779 exhibits a favorable PK profile in nude mice, an iv half-life of 1 h, moderate distribution (Vd=2.6 L/kg), and measurable oral exposure with an estimated bioavailability of 33%. It demonstrates antitumor efficacy in the CWR22 xenograft model; oral dosing for 14 days at 30 mg/kg bid results in tumor stasis and partial regressions in 5/10 animals[1]. CEP-33779 administration results in an almost complete shrinkage of tumors in most animals; few remaining tumor nodules were small, poorly vascularized, and had a necrotic appearance. CEP-33779 suppressed activation of NF-κB in tumors[2].

References

[1].Dugan BJ, et al. A selective, orally bioavailable 1,2,4-triazolo[1,5-a]pyridine-based inhibitor of Janus kinase 2 for use in anticancer therapy: discovery of CEP-33779. J Med Chem. 2012 Jun 14;55(11):5243-54.

[2].Seavey MM, et al. Therapeutic efficacy of CEP-33779, a novel selective JAK2 inhibitor, in a mouse model of colitis-induced colorectal cancer. Mol Cancer Ther. 2012 Apr;11(4):984-93.

[3].Tang SJ, et al. CEP-33779 antagonizes ATP-binding cassette subfamily B member 1 mediated multidrug resistance by inhibiting its transport function. Biochem Pharmacol. 2014 Sep 15;91(2):144-56.