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MedKoo CAT#: 200786
Description: Momelotinib, also known as CYT387, is an inhibitor of Janus kinases JAK1 and JAK2, acting as an ATP competitor with IC50 values of 11 and 18 nM, respectively. The inhibitor is significantly less active towards other kinases, including JAK3 (IC50 = 0.16 μM). As of 2011, CYT387 is being developed as a drug for myelofibrosis and currently undergoes Phase I/II clinical trials. Additional potential treatment indications for CYT387 include other myeloproliferative neoplasms, cancer (solid and liquid tumors) and inflammatory conditions.
MedKoo Cat#: 200786
Name: Momelotinib (CYT387)
Chemical Formula: C23H22N6O2
Exact Mass: 414.18042
Molecular Weight: 414.46
Elemental Analysis: C, 66.65; H, 5.35; N, 20.28; O, 7.72
Synonym: CTY387; CYT-387; CYT 387; CYT11387; CYT-11387; CYT 11387; Momelotinib.
IUPAC/Chemical Name: N-(cyanomethyl)-4-(2-((4-morpholinophenyl)amino)pyrimidin-4-yl)benzamide.
SMILES Code: O=C(NCC#N)C1=CC=C(C2=NC(NC3=CC=C(N4CCOCC4)C=C3)=NC=C2)C=C1
CYT387 is an ATP-competitive small molecule that potently inhibits JAK1/JAK2 kinases (IC(50)=11 and 18 nM, respectively), with significantly less activity against other kinases, including JAK3 (IC(50)=155 nM). CYT387 inhibits growth of Ba/F3-JAK2V617F and human erythroleukemia (HEL) cells (IC(50) approximately 1500 nM) or Ba/F3-MPLW515L cells (IC(50)=200 nM), but has considerably less activity against BCR-ABL harboring K562 cells (IC=58 000 nM). Cell lines harboring mutated JAK2 alleles (CHRF-288-11 or Ba/F3-TEL-JAK2) were inhibited more potently than the corresponding pair harboring mutated JAK3 alleles (CMK or Ba/F3-TEL-JAK3), and STAT-5 phosphorylation was inhibited in HEL cells with an IC(50)=400 nM. Furthermore, CYT387 selectively suppressed the in vitro growth of erythroid colonies harboring JAK2V617F from polycythemia vera (PV) patients, an effect that was attenuated by exogenous erythropoietin. Overall, research data indicate that the JAK1/JAK2 selective inhibitor CYT387 has potential for efficacious treatment of MPN harboring mutated JAK2 and MPL alleles. [source: Pardanani A, Lasho T, Smith G, Burns CJ, Fantino E, Tefferi A. CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. Leukemia. 2009 Aug;23(8):1441-5. Epub 2009 Mar 19. or http://www.ncbi.nlm.nih.gov/pubmed/19295546]
1: Durmus S, Xu N, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH. P-glycoprotein (MDR1/ABCB1) and breast cancer resistance protein (BCRP/ABCG2) restrict brain accumulation of the JAK1/2 inhibitor, CYT387. Pharmacol Res. 2013 Oct;76:9-16. doi: 10.1016/j.phrs.2013.06.009. Epub 2013 Jul 1. PubMed PMID: 23827160.
2: Pardanani A, Laborde RR, Lasho TL, Finke C, Begna K, Al-Kali A, Hogan WJ, Litzow MR, Leontovich A, Kowalski M, Tefferi A. Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. Leukemia. 2013 Jun;27(6):1322-7. doi: 10.1038/leu.2013.71. Epub 2013 Mar 5. PubMed PMID: 23459451; PubMed Central PMCID: PMC3677140.
3: Sparidans RW, Durmus S, Xu N, Schinkel AH, Schellens JH, Beijnen JH. Liquid chromatography-tandem mass spectrometric assay for the JAK2 inhibitor CYT387 in plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2012 May 1;895-896:174-7. doi: 10.1016/j.jchromb.2012.03.021. Epub 2012 Mar 23. PubMed PMID: 22476054.
4: Monaghan KA, Khong T, Burns CJ, Spencer A. The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cells. Leukemia. 2011 Dec;25(12):1891-9. doi: 10.1038/leu.2011.175. Epub 2011 Jul 26. PubMed PMID: 21788946.
5: Tyner JW, Bumm TG, Deininger J, Wood L, Aichberger KJ, Loriaux MM, Druker BJ, Burns CJ, Fantino E, Deininger MW. CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. Blood. 2010 Jun 24;115(25):5232-40. doi: 10.1182/blood-2009-05-223727. Epub 2010 Apr 12. PubMed PMID: 20385788; PubMed Central PMCID: PMC2892953.
6: Pardanani A, Lasho T, Smith G, Burns CJ, Fantino E, Tefferi A. CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. Leukemia. 2009 Aug;23(8):1441-5. doi: 10.1038/leu.2009.50. Epub 2009 Mar 19. PubMed PMID: 19295546.