tcsc0107 AT9283

AT9283 is a multi-targeted inhibitor with IC₅₀s of 1.2 nM, 1.1 nM for JAK2 and JAK3, respectively, and is also potent to Aurora A, Aurora B and Abl(T315I).

IC50 & Target: IC50: 1.2 nM (JAK2), 1.1 nM (JAK3), 3 nM (Aurora A), 3 nM (Aurora B)^[1]

In Vitro: AT9283 leads to a clear polyploid phenotype by inhibiting the activity of Aurora B kinase in HCT116 cells with IC₅₀ of 30 nM. Furthermore, AT9283 also produces the potent inhibition on HCT116 colony formation^[1]. AT9283 induces apoptosis in a dose and time dependent manner and inhibits cell proliferation with an IC₅₀ < 1 μM in B-NHL cell lines^[2]. AT9283 inhibits growth, induces dose dependent cytotoxicity, and inhibits STAT3 signaling pathway in MM cell lines. T9283 inhibits phospho Histone H3 and phospho Aurora A at Thr 288. AT9283 increases G2/M phase and induces apoptosis of MM cells in a time-dependent manner^[3].

In Vivo: In HCT116 human colon carcinoma xenograft bearing mice, AT9283 treatment (15 mg/kg and 20 mg/kg) for 16 days results in a significant tumor growth inhibition of 67% and 76%, respectively. In addition, AT9283 also exhibits a significantly longer half-life in tumors (2.5 hours) compared with plasma (0.5 hour) and modest oral bioavailability in mice^[1]. AT9283 (15 mg/kg) and docetaxel (10 mg/kg) alone has modest anti-tumor activity. T9283 at 20 mg/kg and AT9283 (15 or 20 mg/kg) plus docetaxel (10 mg/kg) demonstrate a statistically significant tumor growth inhibition and enhance survival inmouse xenograft model of mantle cell lymphoma^[2]. AT9283 (45 mg/kg, i.p.) inhibits tumor growth in mice. Two cycles of AT9283 45 mg/kg 14 hours after drug administration confirm decreased expression of phospho-Histone H3 and Aurora B in treated animals^[3].