1-Cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea, AT 9283, AT-9283, N-Cyclopropyl-N′-[3-[6-(4-morpholinylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]-urea
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A multitargeted kinase inhibitor with in vivo anticancer efficacy and potent activity against Abl, aurora kinase A/B and JAK2/3.
AT9283 has also been shown to accelerate growth arrest in various xenograft models.[1]
AT9283 is an ATP site-targeting pyrazole-benzimidazole-based molecule with inhibitory potency against multiple kinases, most notably Aurora A/B (IC50 ≤3.0 nM), JAK2/3 (IC50 = 1.2/1.1 nM), Abl T315I (IC50 = 4 nM), GSK3β, FGFR2, VEGFR3 (Flt4), Mer, Ret, Rsk2/3, Tyk2, Yes (IC50 = 1-10 nM). AT9283 also inhibits 72 other kinases/mutations at a reduced potency (IC50 = 10-30 nM against 14, 30-100 nM against 21, 100-300 against 37 targets), while displaying an IC50 >300 nM toward 144 other kinase targets. AT9283 inhibits the growth/survival of multiple solid tumor cell lines in vitro (IC50 = 7.7-20 nM) and shows anti-cancer efficacy in mice via i.p. injection in vivo (67% and 76%HCT116 tumor growth inhibition on day 16, respectively, with 15 and 20 mg/kg b.i.d., two-day on and two-day off; >95% inhibition of Ba/F3 ETV6-JAK2 leukemia proliferation on day 12 with 10 mg/kg b.i.d. on days 2–5 and 8–12).
Structure (London, England : 1993), 24(3), 401-411 (2016-02-09)
The highly diverse Numb-associated kinase (NAK) family has been linked to broad cellular functions including receptor-mediated endocytosis, Notch pathway modulation, osteoblast differentiation, and dendrite morphogenesis. Consequently, NAK kinases play a key role in a diverse range of diseases from Parkinson's
British journal of haematology, 150(1), 46-57 (2010-05-29)
Constitutive activation of Janus kinase (Jak) 2 is the most prevalent pathogenic event observed in the myeloproliferative disorders (MPD), suggesting that inhibitors of Jak2 may prove valuable in their management. Inhibition of the Aurora kinases has also proven to be
Increasing evidence suggests key roles for members of the mammalian Sterile20-like (MST) family of kinases in many aspects of biology. MST3 is a member of the STRIPAK complex, the deregulation of which has recently been associated with cancer cell migration
ACS chemical biology, 11(8), 2195-2205 (2016-05-27)
The accumulation of unfolded proteins under endoplasmic reticulum (ER) stress leads to the activation of the multidomain protein sensor IRE1α as part of the unfolded protein response (UPR). Clustering of IRE1α lumenal domains in the presence of unfolded proteins promotes
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