MedKoo product information:

CYT387

CYT387 is an orally-administered, potent, selective inhibitor of the JAK1 and JAK2 kinases, enzymes which have been implicated in a number of disorders including myeloproliferative neoplasms (MPNs), inflammatory diseases and certain cancers. The molecule possesses an excellent selectivity and safety profile with minimal off-target activity, a favorable pharmacokinetic and toxicological profile, and the prospect of limited drug/drug interactions. Data from MPN patient samples demonstrate suppression of JAK enzyme over-activity. CYT387 was developed by Australian biotech company Cytopia Research Pty Ltd, and is now part of the YM BioSciences development program. [source: http://www.ymbiosciences.com].

Current developer:    Cytopia Research Pty Ltd and YM BioSciences.

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: Pardanani A, Vannucchi AM, Passamonti F, Cervantes F, Barbui T, Tefferi A. JAK inhibitor therapy for myelofibrosis: critical assessment of value and limitations. Leukemia. 2010 Nov 16. [Epub ahead of print] PubMed PMID: 21079613.

2: 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. Epub 2010 Apr 12. PubMed PMID: 20385788; PubMed Central PMCID: PMC2892953.

3: Burns CJ, Bourke DG, Andrau L, Bu X, Charman SA, Donohue AC, Fantino E, Farrugia M, Feutrill JT, Joffe M, Kling MR, Kurek M, Nero TL, Nguyen T, Palmer JT, Phillips I, Shackleford DM, Sikanyika H, Styles M, Su S, Treutlein H, Zeng J, Wilks AF. Phenylaminopyrimidines as inhibitors of Janus kinases (JAKs). Bioorg Med Chem Lett. 2009 Oct 15;19(20):5887-92. Epub 2009 Aug 23. PubMed PMID: 19762238.

4: 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. PubMed PMID: 19295546.

5: Sharma A, Rana DN, Desai M. Cytomorphological evaluation of a small round blue cell tumour of the head and neck. Cytopathology. 2007 Jun;18(3):197-9. PubMed PMID: 17573767.