AZD-1208 is a potent and selective pan-Pim kinase inhibitor which demonstrates efficacy in preclinical models of acute myeloid leukemia. AZD1208 inhibited the growth of 5 of 14 acute myeloid leukemia (AML) cell lines tested, and sensitivity correlates with Pim-1 expression and STAT5 activation. AZD1208 causes cell cycle arrest and apoptosis in MOLM-16 cells, accompanied by a dose-dependent reduction in phosphorylation of Bcl-2 antagonist of cell death, 4EBP1, p70S6K, and S6, as well as increases in cleaved caspase 3 and p27.AZD1208 inhibits the growth of MOLM-16 and KG-1a xenograft tumors in vivo with a clear pharmacodynamic-pharmacokinetic relationship. AZD1208 also potently inhibits colony growth and Pim signaling substrates in primary AML cells from bone marrow that are Flt3 wild-type or Flt3 internal tandem duplication mutant.AZD1208 inhibited tumorigenesis in tissue recombinants, Myc-CaP, and human PC xenograft models.AZD1208 suppressed multiple protumorigenic pathways, including the MYC gene program.
|Cell lines||EOL-1, KG-1a, Kasumi-3, MV4-11, and MOLM-16 cells|
|Preparation method||For proliferation assays, cells were plated at 5,000 to 20,000 cells per well in 96 well plates overnight before treatment for 72 hours with serially diluted compound or vehicle DMSO. Cell viability was measured after the addition of 10 μL Alamar Blue (Invitrogen) for 4 hours at 37˚C. The GI50 was determined by calculating growth at each dose relative to vehicle treated cells and cell viability at the time of treatment.|
|Incubation time||72 h|
|Animal models||Female CB17 SCID mice bearing MOLM-16 cells or KG-1a cells xenografts model|
|Formulation||0.5% hydroxypropyl methylcellulose|
|Dosages||3, 10 and 30mg/kg daily for 14 days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO >28 mg/ml|
PIM kinase inhibitor AZD1208 for treatment of MYC-driven prostate cancer.
Kirschner AN, et al. J Natl Cancer Inst. 2014 Dec 13;107(2). PMID: 25505253.
The Pim-1 protein kinase is an important regulator of MET receptor tyrosine kinase levels and signaling.
Cen B, et al. Mol Cell Biol. 2014 Jul;34(13):2517-32. PMID: 24777602.
AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia.
Keeton EK, et al. Blood. 2014 Feb 6;123(6):905-13. PMID: 24363397.
|Related Pim Products|
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|TCS PIM-1 1
TCS PIM-1 1 is a potent and selective ATP-competitive Pim-1 kianse inhibitor with IC50 of 50 nM, displays good selectivity over Pim-2 and MEK1/MEK2(IC50s > 20,000 nM).
CX-6258 is a potent, orally efficacious Pim 1/2/3 kinase(IC50=5 nM/25 nM/16 nM) inhibitor with excellent biochemical potency and kinase selectivity.
SMI-4a is a potent inhibitor of Pim1 with IC50 of 17 nM, modest potent to Pim-2, does not significantly inhibit other serine/threonine- or tyrosine-kinases.
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