AT-9283

A multi-targeted kinase inhibitor with potent activity against Aurora A, Aurora B, JAK2, JAK3, and ABL (T315I) with IC50 of 3, 3, 1.2, 1.1, and 4 nM, respectively; also inhibits GSK-3β, FGFR2, VEGFR3, Mer, etc. (IC50=1-10 nM) ; potently inhibits proliferation and Jak2-related signalling in Jak2-dependent cell lines, demonstrates significant therapeutic potential in vivo in an ETV6-JAK2 (TEL-JAK2) murine leukaemia model. Blood Cancer Phase 2 Clinical (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.AT9283 induces apoptosis in a dose and time dependent manner and inhibits cell proliferation with an IC50 < 1 μM in B-NHL cell lines.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. (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.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.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.