Cat. No. Name Size Price Add Cart
KI0380LY27845445 mg$272
LY278454410 mg$512
LY278454450 mg$1552
LY2784544200 mg$3952

Chemical Characteristic

Product NameLY2784544
CAS No.1229236-86-5
Molecular Weight 469.94
FormulaC23H25ClFN7O
Chemical Name3-(4-chloro-2-fluorobenzyl)-2-methyl-N-(3-methyl-1H-pyrazol-5-yl)-8-(morpholinomethyl)imidazo[1,2-b]pyridazin-6-amine
Smilesc12c(cc(nn1c(c(n2)C)Cc1c(cc(cc1)Cl)F)Nc1n[nH]c(c1)C)CN1CCOCC1
Chemical Structure

Biological activities

LY2784544 has been identified as being highly selective for JAK 2-V617F and has advanced into human clinical trials for the treatment of several myeloproliferative disorders.[1] LY2784544, a new promising molecule, provides a potent inhibition of the JAK2 (V617F)??TAT5 signaling at a concentration that is 41-fold lower than that required to inhibit interleukin (IL)-3-activated wild type JAK2-STAT5 signaling: IC50 nM for JAK2 (V617F) vs. 2.26 μM for JAK2-WT. LY2784544 decreases the BFU-E and CFU-GM growth in therapy-naive JAK2 (V617F)-positive cells from polycythemia vera patients in a dose-dependent manner without complete inhibition of all colonies.[2] Meanwhile, LY2784544 selectively inhibits the JAK2 V617F-driven cell proliferation with an IC50 of 68 nM. In Ba/F3 cell model, LY2784544 inhibits JAK2 V617F signaling correlated well with the induction of apoptosis with EC50 of 0.11 µM. Consistent with the observed apparent selectivity for the V617F mutant and reduced sensitivity against wild type JAK2, a lower potency is observed with LY2784544 in the IL-3-dependent cell proliferation assay with an IC50 of 1.36 µM. LY2784544 shows less effective inhibition of IL-2 dependent JAK3-STAT5 signaling in NK-92 cells with an IC50 of 0.94 µM. LY2784544 selectively reduces JAK2 V617F tumor cell burden with no effect on erythroid progenitor cells. LY2784544 has the potential to induce apoptosis in JAK2 V617F malignant clones while potentially minimizing unintended effects on the normal hematopoietic progenitor cells. In vivo, LY2784544 effectively inhibits STAT5 phosphorylation in Ba/F3-JAK2 V617F-GFP ascites tumor cells with a threshold effective dose 50 (TAED50) of 12.7 mg/kg. LY2784544 also significantly reduces Ba/F3-JAK2 V617F-GFP tumor burden in the JAK2 V617F-induced myeloproliferative neoplasm (MPN) model with a TAED50 of 13.7 mg/kg after oral treatment (BID) for 14 days. Besides, LY2784544 selectively reduces Ba/F3-JAK2 V617F-GFP tumor cells with no effect on CD71/Ter119 positive erythroid progenitors in spleens of SCID mice after oral treatment (BID) for 7 days. [3]

References

[1] David M, et al. Development and a Practical Synthesis of the JAK2 Inhibitor LY2784544. Org.Process.Res.Dev. 2012, 16(1): 70-81.
[2] Francesco P, et al. New generation small-molecule inhibitors in myeloproliferative neoplasms. Curr Opin Hematol. 2012, 19(2): 117-123.
[3] Ma L, et al. 53rd ASH Annual Meeting and Exposition, 2011, Abstract 4087.

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