AKI603

AKI603 is an inhibitor of Aurora kinase A (AurA) , with an IC 50 of 12.3 nM. AKI603 is developed to overcome resistance mediated by BCR-ABL-T315I mutation. AKI603 exhibits strong anti-proliferative activity in leukemic cells In Vitro 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 (IC 50 =2.04), BT549 (IC 50 =0.86), MCF-7 (IC 50 =0.97), MCF-7-Epi (IC 50 =21.01), Sk-br-3 (IC 50 =0.73), MDA-MB-231 (IC 50 =3.49), MDA-MB-453 (MTT, IC 50 =0.18; Cell counting, IC 50 =0.19), MDA-MB-468 (MTT, IC 50 =0.15; Cell counting, IC 50 =0.17). MCE has not independently confirmed the accuracy of these methods. They are for reference only. Cell Proliferation AssayCell 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 AnalysisCell 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 AnalysisCell 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. In Vivo 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 C max (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). MCE has not independently confirmed the accuracy of these methods. They are for reference only. 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%), C max (202.4 μg/L), T 1/2 (8.9 h) Form:Solid IC50& Target:Aurora A 12.3 nM (IC 50 )

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