生物活性

• 靶点

  JAK2 (V617F) Ki:0.245nM

  JAK2 IC50:3nM

• 描述The JAK/STAT3 pathway is activated by various cancer types, including glioma, and blockade of the pathway induces cell death in cancer cells. The Janus family kinases (JAKs), JAK1, JAK2, JAK3, and TYK2, are involved in cell growth, survival, development, and differentiation of a variety of cells, particularly immune cells and hematopoietic cells. LY2784544 is a potent, selective and ATP-competitive inhibitor of janus kinase 2 (JAK2) tyrosine kinase with IC₅₀ of 3 nM. Gandotinib (LY2784544) also inhibits FLT3, FLT4, FGFR2, TYK2, and TRKB with IC₅₀ of 4, 25, 32, 44, and 95 nM, respectively and shows increased potency for the JAK2 _V617F mutation. LY2784544 effectively inhibited JAK2 _V617F -driven signaling and cell proliferation in Ba/F3 cells with IC₅₀ of 20 and 55 nM, respectively. In comparison, LY2784544 was much less potent at inhibiting interleukin-3-stimulated wild-type JAK2-mediated signaling and cell proliferation with IC₅₀ of 1183 and 1309 nM, respectively. In a mouse ascitic tumor model with Ba/F3-JAK2 _V617F-GFP cells, LY2784544 was administered once by oral gavage at a dose of 2.5, 5.0, 10.0, 20.0, 40.0, or 80.0 mg/kg to severe combined immunodeficiency mice to measure the inhibition of STAT5 phosphorylation. The result demonstrated that LY2784544 possess good inhibiting effect at STAT5 phosphorylation at indicated concentrations. LY2784544 also potently inhibited STAT5 phosphorylation in Ba/F3 cells expressing JAK2_V617F across a concentration range from 50 nM–20 μM^[3]. LY2784544 discovered in a focused screen at low micromolar concentrations, prevented Tf endocytosis as well as trypanosome proliferation with GI50 1.0-3.1 μM^[4].
• 作用机制LY2784544 targets the adenosine triphosphate (ATP) binding site at the TK domain, thus affecting both mutated and wild-type kinases.
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01134120	Myeloproliferative Disorders ... more >> Thrombocythemia, Essential Polycythemia Vera Primary Myelofibrosis Collapse <<	Phase 1	Completed	-	United States, Texas ... more >> For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Houston, Texas, United States, 77030 United States, Utah For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Salt Lake City, Utah, United States, 84132 Collapse <<
  NCT01577355	Healthy Male Volunteers	Phase 1	Completed	-	United States, Wisconsin ... more >> For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Madison, Wisconsin, United States, 53704 Collapse <<
  NCT01594723	Neoplasms, Hematologic	Phase 2	Active, not recruiting	December 31, 2019	-

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• 参考文献

• [1] Douglas JJ, Cole KP, Stephenson CR. Photoredox catalysis in a complex pharmaceutical setting: toward the preparation of JAK2 inhibitor LY2784544. J Org Chem. 2014 Dec 5;79(23):11631-43.

  [2] Ma L, Clayton JR, et al. Discovery and characterization of LY2784544, a small-molecule tyrosine kinase inhibitor of JAK2V617F. Blood Cancer J. 2013 Apr 12;3:e109.

  [3] Ma L, Clayton JR, Walgren RA, Zhao B, Evans RJ, Smith MC, Heinz-Taheny KM, Kreklau EL, Bloem L, Pitou C, Shen W, Strelow JM, Halstead C, Rempala ME, Parthasarathy S, Gillig JR, Heinz LJ, Pei H, Wang Y, Stancato LF, Dowless MS, Iversen PW, Burkholder TP. Discovery and characterization of LY2784544, a small-molecule tyrosine kinase inhibitor of JAK2V617F. Blood Cancer J. 2013 Apr 12;3(4):e109. doi: 10.1038/bcj.2013.6. PMID: 23584399; PMCID: PMC3641321.}

  [4] Santos FP, Verstovsek S. JAK2 inhibitors for myelofibrosis: why are they effective in patients with and without JAK2V617F mutation? Anticancer Agents Med Chem. 2012 Nov;12(9):1098-109. doi: 10.2174/187152012803529727. PMID: 22583424.