AZD 1480

AZD 1480 is a potent JAK2 inhibitor that blocks signaling (IC₅₀ = 58 nM at 5 mM ATP) and proliferation of JAK2-expressing cell lines (GI₅₀ = 60 nM).^1,2 It is selective for JAK2 over other JAK family members as well as a panel of related kinases.² AZD 1480 also inhibits the growth of cells expressing the V617F mutant of JAK2 (GI₅₀ = 60 nM).² It reversibly blocks JAK2-mediated phosphorylation of STAT3 and STAT5.² AZD 1480 displays good pharmacokinetics in vivo, inhibits STAT3 and STAT5 activation in vivo, and suppresses tumorigenesis in mouse xenografts harboring constitutive STAT3 activity.^1,2 In addition to suppressing myeloma cell growth and survival, AZD 1480 reduces angiogenesis and metastasis in vitro and in human xenograft tumor models.^3,4

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1. Hedvat, M., Huszar, D., Herrmann, A., et al. The JAK2 inhibitor AZD1480 potently blocks stat3 signaling and oncogenesis in solid tumors. Cancer Cell 16(6), 487-497 (2009).

2. Ioannidis, S., Lamb, M.L., Wang, T., et al. Discovery of 5-chloro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)-pyrimidine-2,4-diamine (AZD1480) as a novel inhibitor of the Jak/Stat pathway. J. Med. Chem. 54(1), 262-276 (2010).

3. Scuto, A., Krejci, P., Popplewell, L., et al. The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival. Leukemia 25(3), 538-550 (2011).

4. Xin, H., Herrmann, A., Reckamp, K., et al. Antiangiogenic and antimetastatic activity of JAK inhibitor AZD1480. Cancer Res. 71(21), 6601-6610 (2011).