AKI603 is a novel small molecule inhibitor of Aurora kinase A (AurA)(IC50 = 12.3 nM). AKI603 is developed to overcome resistance mediated by BCR-ABL-T315I mutation. AKI603 exhibits strong anti-proliferative activity in leukemic cells[1][2].

Aurora A:12.3 nM

AKI603抑制伊马替尼耐药性CML细胞的增殖和集落形成[1]。AKI603抑制AurA，可诱导BCR-ABL野生型和T315I突变细胞的白血病细胞衰老[1]。AKI603还展示了对乳腺癌细胞增殖的抑制活性，以及在NB4, K562和Jurkat细胞系中，随剂量增加显著地抑制AurA的磷酸化，而AurA总蛋白水平未发生改变[1]。

AKI603通过口服给药展现出中等的口服生物利用度和Cmax[3]。经静脉给药后，AKI603展现出终末消除半衰期[3]。AKI603能够抑制裸鼠中异种移植的KBM5-T315I细胞的生长[1]。

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)[2]. AKI603 (0.039-0.6 μM; 48 hours) extensively inhibits proliferation of leukemia cells[1]. 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[1]. AKI603 inhibits the proliferation and colony formation of imatinib resistant CML cells[1]. 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[1]. Inhibition of AurA by AKI603 induces leukemia cell senescence in both BCR-ABL wild type and T315I mutation cells[1].

AKI603 (12.5-25?mg/kg; i.p.; every 2 days; for 14 days; female BALB/c nude mice with KBM5-T315I cells xenografted) abrogates the growth of tumors[1]. Pharmacokinetic Analysis shows that AKI603 exhibits moderate oral bioavailability (rat 28.7%) and Cmax (rat 202.4 μg/L) following oral administration (rat 25 mg/kg)[3]. AKI603 also exhibits terminal elimination half-life (rat 8.9 h) following intravenous administration (rat 2.5 mg/kg)[3].