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AZD1208 hydrochloride is a novel, orally bioavailable, highly selective PIM kinases inhibitor. PIM[1]

AZD1208 hydrochloride shows good antiproliferative activity in a megakaryoblastic leukemia cell line, MOLM-16, with GI50 values less than 100 nM[1]. AZD1208 hydrochloride (10 μM) inhibits the growth of Ramos cells, and at 1 μM, strongly inhibits PIM kinases in all cells at 1 μM. AZD1208 hydrochloride induces apoptosis, and PIM2 knockdown is mainly associated with an alteration of the cell cycle[2]. The combination of AZD1208 hydrochloride and AZD2014 rapidly activates AMPKα, a negative regulator of translation machinery through mTORC1/2 signaling in AML cells; profoundly inhibits AKT and 4EBP1 activation; and suppresses polysome formation[3].

[1]. Dakin LA, et al. Discovery of novel benzylidene-1,3-thiazolidine-2,4-diones as potent and selective inhibitors of the PIM-1, PIM-2, and PIM-3 protein kinases. Bioorg Med Chem Lett. 2012 Jul 15;22(14):4599-604. [2]. Kreuz S, et al. Loss of PIM2 enhances the anti-proliferative effect of the pan-PIM kinase inhibitor AZD1208 in non-Hodgkin lymphomas. Mol Cancer. 2015 Dec 8;14:205. [3]. Harada M, et al. The novel combination of dual mTOR inhibitor AZD2014 and pan-PIM inhibitor AZD1208 inhibits growth in acute myeloid leukemia via HSF pathway suppression. Oncotarget. 2015 Nov 10;6(35):37930-47.

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