AT9283

Names

[ Name ]:
AT9283

[Synonym ]:
AT9283
1-Cyclopropyl-3-{3-[5-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}harnstoff
1-Cyclopropyl-3-{3-[5-(4-morpholinylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}urea
1-cyclopropyl-3-{3-[5-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}urea
S1134_Selleck
Urea, N-cyclopropyl-N'-[3-[5-(4-morpholinylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]-
cc-56
AT-9283,AT 9283
AT-9283

Biological Activity

[Description]:

AT9283 is a multitargeted kinase inhibitor which potently inhibits aurora kinase A/B, JAK2/3 (IC50=1.2 nM, 1.1 nM).

[Related Catalog]:

Signaling Pathways >> Cell Cycle/DNA Damage >> Aurora Kinase

Signaling Pathways >> Epigenetics >> Aurora Kinase

Signaling Pathways >> Autophagy >> Autophagy

Signaling Pathways >> Epigenetics >> JAK

Signaling Pathways >> JAK/STAT Signaling >> JAK

Signaling Pathways >> Stem Cell/Wnt >> JAK

Research Areas >> Cancer

[Target]

JAK2:1.2 nM (IC50)

JAK3:1.1 nM (IC50)

Aurora A:3 nM (IC50)

Aurora B:3 nM (IC50)

Abl (T315I):4 nM (IC50)

[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].

[Cell Assay]

Lymphoma cells are seeded at 8,000 per well in 96-well culture plates and allowed to grow for 24 hr followed by the desired treatment with increasing concentrations of the indicated agents for 4 days. Viable cell densities are determined using a CellTiter 96 Cell Proliferation Assay. The IC50 values are estimated by Calcusyn software.

[Animal admin]

SCID mice are injected with 1×107 Granta-519 MCL cells subcutaneously into the right hind flank. When tumors reached a volume of appr 60-100 mm3, mice are divided randomly (pair-matched) into six test groups with 12 mice per cohort: control group (saline), AT9283 (15 mg/kg IP Q1D, 5 days a week × 3 weeks) group, AT9283 (20 mg/kg IP Q1D, 5 days a week × 3 weeks) group, docetaxel (10 mg/kg IV Q1W × 3 weeks) group, AT9283 (15 mg/kg IP Q1D, 5 days a week × 3 weeks) + docetaxel (10 mg/kg IV Q1W × 3 weeks) group and AT9283 (20 mg/kg IP Q1D, 5 days a week × 3 weeks) + docetaxel (10 mg/kg IV Q1W × 3 weeks) group. The length (L) and width (W) of the subcutaneous tumors are measured by calipers and the tumor volume (TV) is calculated as: TV=(L × W2)/2. Mice are sacrificed at the end of study and overall survival for each cohort is analyzed by Kaplan–Meier method.

[References]

[1]. Howard S, et al. Fragment-Based Discovery of the Pyrazol-4-yl Urea (AT9283), a Multitargeted Kinase Inhibitor with Potent Aurora Kinase Activity. Journal of Medicinal Chemistry (2009), 52(2), 379-388.

[2]. Qi W, et al. AT9283, a novel aurora kinase inhibitor, suppresses tumor growth in aggressive B-cell lymphomas. Int J Cancer. 2012 Jun 15;130(12):2997-3005.

[3]. Santo L, et al. Antimyeloma activity of a multitargeted kinase inhibitor, AT9283, via potent Aurora kinase and STAT3 inhibition either alone or in combination with lenalidomide. Clin Cancer Res. 2011 May 15;17(10):3259-71

[Related Small Molecules]