AKI-603

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

一种新型小分子 Aurora A 激酶抑制剂，IC50 为 12.3 nM，也能在较小程度上抑制 Aurora B 激酶活性。

A novel small molecule Aurora A kinase inhibitor with IC50 of 12.3 nM, also inhibits Aurora B kinase activity to a less extent; disrupts normal spindle structure, and induces cell-cycle arrest; suppresses stem cell properties in breast cancer cells, and also suppresses the expression of self-renewal genes (β-catenin, c-Myc, Sox2, and Oct4); reduces xenograft tumor growth after intragastric administration.

AKI603 (0.039-0.6 μM; 48 hours) extensively inhibits proliferation of leukemia cells.AKI603 (0.039-0.6 μM; 48 hours) significantly inhibits the phosphorylation of AurA in NB4, K562, and Jurkat cell lines in a dose-dependent manner while the level of total AurA protein is not changed.AKI603 inhibits the proliferation and colony formation of imatinib resistant CML cells.AKI603 (0.3-0.6 μM; 48 hours) inhibits cell proliferation and colony formation capacities in imatinib-resistant CML cells by inducing cell cycle arrest with polyploidy accumulation.Inhibition of AurA by AKI603 induces leukemia cell senescence in both BCR-ABL wild type and T315I mutation cells.AKI603 exhibits inhibitory activities on breast cancer cell proliferation, such as SUM149 (IC50=2.04), BT549 (IC50=0.86), MCF-7 (IC50=0.97), MCF-7-Epi (IC50=21.01), Sk-br-3 (IC50=0.73), MDA-MB-231 (IC50=3.49), MDA-MB-453 (MTT, IC50=0.18; Cell counting, IC50=0.19), MDA-MB-468 (MTT, IC50=0.15; Cell counting, IC50=0.17). Cell Proliferation Assay Cell Line:U937 cells, HL-60 cells, NB4 cells, KBM5 cells, K562 cells, Jurkat cells Concentration:0.039 μM, 0.078 μM, 0.16 μM, 0.3 μM, 0.6 μM Incubation Time:48 hours Result:Inhibited all the tested cell lines.Western Blot Analysis Cell Line:NB4 cells, K562 cells, Jurkat cells Concentration:0.039 μM, 0.078 μM, 0.16 μM, 0.3 μM, 0.6 μM Incubation Time:48 hours Result:Inhibited the phosphorylation of AurA Thr288 (p-AurA).Cell Cycle Analysis Cell Line:K562, K562/G, 32D-p210 and 32D-T315I cells Concentration:0.3 μM, 0.6 μM Incubation Time:48 hours Result:Induced polyploidization in the tested cells.

AKI603 (12.5-25?mg/kg; i.p.; every 2 days; for 14 days) abrogates the growth of xenografted KBM5-T315I cells in nude mice.AKI603 exhibits moderate oral bioavailability (rat 28.7%) and Cmax (rat 202.4 μg/L) following oral administration (rat 25 mg/kg).AKI603 exhibits terminal elimination half-life (rat 8.9 h) following intravenous administration (rat 2.5 mg/kg). Animal Model:Female BALB/c nude mice, with KBM5-T315I cells xenografted Dosage:12.5?mg/kg, 25?mg/kg Administration:Intraperitoneal injection, every 2 days, for 14 days Result:Significantly inhibited the growth of tumors.Animal Model:SD rats (220-280 g) Dosage:2.5 mg/kg for i.v.; 25 mg/kg for p.o. (Pharmacokinetic Analysis) Administration: Intravenous injection, oral administration Result:Oral bioavailability (28.7%), Cmax (202.4 μg/L), T1/2 (8.9 h)

AKI603

Cell Cycle/DNA Damage

Aurora Kinase

Aurora Kinase

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1432515-73-5

409.454

C19H23N9O2

>98% (HPLC)

In Vitro:?DMSO : 125 mg/mL (305.29 mM)

O=[N+](C1=CC=C(NC2=NC(N3CCN(C)CC3)=CC(NC4=NNC(C)=C4)=N2)C=C1)[O-]

N4-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-N2-(4-nitrophenyl)pyrimidine-2,4-diamine

(-20℃)

With Ice Pack

≥ 2 years