LY2784544

LY2784544 is a potent, selective inhibitor of JAK2 with IC50 value of 3 nM.[1]
Janus kinase 2 (JAK2) belongs to the Janus kinase family and is a member of the type II cytokine receptor family. It is a non-receptor tyrosine kinase. The JAK2 mutation (V617F) within the autoinhibitory pseudokinase domain results in a gain-of-function activation of JAK2.The JAK2V617F mutant results in subsequent phosphorylation of signal transducer and activator of transcription 5 (STAT5). Then, STAT5 regulates the transcription of genes associated with cell growth, death and differentiation. The JAK2V617F mutant is oncogenic in cells, and sufficient for generating the myeloproliferative neoplasms (MPN) phenotypes in murine models. Mutant JAK2 kinase is an attractive therapeutic target for the therapy of MPNs. To selectively inhibit JAK2V617F but minimizing inhibition of wild-type JAK2 would be an optimal treatment approach.
LY2784544 is a potent and ATP-competitive inhibitor of JAK2 tyrosine kinase. LY2784544 has 8- and 16-fold selectivity for JAK2 than JAK1 and JAK3, respectively. LY2784544 more effective on inhibiting the phosphorylation of STAT5 in Ba/F3-TEL-JAK2 cells than in Ba/F3-TEL- JAK3 and –JAK1 cells with IC 50 of 0.191 (JAK2), 2.904 (JAK1) and 4.744 nM (JAK3). LY2784544 significantly inhibited STAT5 phosphorylation at a concentration range from 50 nM–20 nM in Ba/F3 cells expressing JAK2V617F. On the other hand, LY2784544 showed minimal inhibition of STAT5 phosphorylation at 50 and 200 nM concentrations in IL-3-stimulated Ba/F3 cells which express wild-type JAK2. LY2784544 significantly inhibited the cell proliferation of JAK2V617F-expressing cells with IC50 ＝55 nM. In JAK2V617F-expressing cells, LY2784544 induced apoptosis with EC50±s.d.of 113±0.023 nM measured by Caspase3/7-glo assays.[1]
LY2784544 with a TED50 (threshold effective Dose 50) of 12.7 mg/kg, potently inhibits STAT5 phosphorylation in SCID mice bearing Ba/F3-JAK2V617F-GFP. In mouse hematologic disease model, LY2784544 also dose-dependly reduces Ba/F3-JAK2V617F-GFP tumor burden.[1]
References:
1.Ma L, Clayton JR, Walgren RA, Zhao B, Evans RJ, Smith MC, Heinz-Taheny KM, Kreklau EL, Bloem L, Pitou C et al: Discovery and characterization of LY2784544, a small-molecule tyrosine kinase inhibitor of JAK2V617F. Blood Cancer J 2013, 3:e109.

Photoredox catalysis in a complex pharmaceutical setting: toward the preparation of JAK2 inhibitor LY2784544.[Pubmed:25356724]

J Org Chem. 2014 Dec 5;79(23):11631-43.

We report a detailed investigation into the application of visible light-mediated photocatalysis to a challenging bond construction in a complex pharmaceutical target. The optimized reaction allowed the direct coupling of N-methylmorpholine with an unfunctionalized pyridazine in good yield and selectivity, and with high purity of the product isolated via crystallization. The reaction also facilitated the expedient synthesis of a range of analogues via the use of other commercially available N-methyl substituted tertiary amines, and therefore it represents an attractive tool for medicinal chemistry. Furthermore, a number of other interesting photoredox reactions were discovered during the course of this investigation, such as a formal methylation reaction via C-N bond cleavage, functionalization of C-H bonds alpha to amides, and a visible light-mediated iminium ion reduction.

Discovery and characterization of LY2784544, a small-molecule tyrosine kinase inhibitor of JAK2V617F.[Pubmed:23584399]

Blood Cancer J. 2013 Apr 12;3:e109.

Owing to the prevalence of the JAK2V617F mutation in myeloproliferative neoplasms (MPNs), its constitutive activity, and ability to recapitulate the MPN phenotype in mouse models, JAK2V617F kinase is an attractive therapeutic target. We report the discovery and initial characterization of the orally bioavailable imidazopyridazine, LY2784544, a potent, selective and ATP-competitive inhibitor of janus kinase 2 (JAK2) tyrosine kinase. LY2784544 was discovered and characterized using a JAK2-inhibition screening assay in tandem with biochemical and cell-based assays. LY2784544 in vitro selectivity for JAK2 was found to be equal or superior to known JAK2 inhibitors. Further studies showed that LY2784544 effectively inhibited JAK2V617F-driven signaling and cell proliferation in Ba/F3 cells (IC50=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 (IC50=1183 and 1309 nM, respectively). In vivo, LY2784544 effectively inhibited STAT5 phosphorylation in Ba/F3-JAK2V617F-GFP (green fluorescent protein) ascitic tumor cells (TED50=12.7 mg/kg) and significantly reduced (P<0.05) Ba/F3-JAK2V617F-GFP tumor burden in the JAK2V617F-induced MPN model (TED50=13.7 mg/kg, twice daily). In contrast, LY2784544 showed no effect on erythroid progenitors, reticulocytes or platelets. These data suggest that LY2784544 has potential for development as a targeted agent against JAK2V617F and may have properties that allow suppression of JAK2V617F-induced MPN pathogenesis while minimizing effects on hematopoietic progenitor cells.

Gandotinib (LY2784544) is a potent JAK2 inhibitor 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.

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