CCT241736 is a potent and orally bioavailable dual FLT3 and Aurora kinase inhibitor, which inhibits Aurora kinases (Aurora-A Kd, 7.5 nM, IC50, 38 nM; Aurora-B Kd, 48 nM), FLT3 kinase (Kd, 6.2 nM), and FLT3 mutants including FLT3-ITD (Kd, 38 nM) and FLT3(D835Y) (Kd, 14 nM).
IC50 & Target
Aurora-A
38 nM (IC50)
Aurora-A
7.5 nM (Kd)
Aurora-B
48 nM (Kd)
FLT3
6.2 nM (Kd)
FLT3(D835H)
11 nM (Kd)
FLT3(D835Y)
14 nM (Kd)
FLT3-ITD
38 nM (Kd)
FLT3(K663Q)
5.1 nM (Kd)
FLT3(N841I)
16 nM (Kd)
FLT3(R834Q)
110 nM (Kd)
体外研究 (In Vitro)
CCT241736 (Compound 27e) is a potent and orally bioavailable dual FLT3 and Aurora kinase inhibitor, which inhibits Aurora kinases (Aurora-A Kd, 7.5 nM, IC50, 38 nM, Aurora-B Kd, 48 nM), FLT3 kinase (Kd, 6.2 nM), and FLT3 mutants including FLT3-ITD (Kd, 38 nM) and FLT3(D835Y) (Kd, 14 nM). CCT241736 exhibits antiproliferative activity in a range of human tumor cell lines, such as HCT116 human colon carcinoma (GI50, 0.300 μM), the human FLT3-ITD positive AML cell lines MOLM-13 (GI50, 0.104 μM) and MV4-11 (GI50, 0.291 μM). CCT241736 also inhibits both the autophosphorylation of Aurora-A at T288 (a biomarker for Aurora-A inhibition: IC50, 0.030 μM) and histone H3 phosphorylation at S10 (a biomarker for Aurora-B inhibition: IC50, 0.148 μM), consistent with potent cellular activity versus both Aurora-A and -B. CCT241736 suppresses Aurora-A in MOLM-13 cells with concomitant inhibition of FLT3 signaling[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
体内研究 (In Vivo)
CCT241736 (50, 100 mg/kg, b.i.d, p.o.) dose-dependently suppresses the growth of MV4-11 human tumor xenografts, and completely abolishes the tumors at 100 mg/kg via p.o. administration twice a day[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
分子量
456.37
Formula
C22H23Cl2N7
CAS 号
1402709-93-6
运输条件
Room temperature in continental US; may vary elsewhere.
[1]. Bavetsias V, et al. Optimization of imidazo[4,5-b]pyridine-based kinase inhibitors: identification of a dual FLT3/Aurora kinase inhibitor as an orally bioavailable preclinical development candidate for the treatment of acute myeloid leukemia. J Med Chem. 2012 Oct 25;55(20):8721-34.
Animal Administration [1]
Mice[1] Female adult CrTacNCr-Fox1(nu) athymic mice are implanted subcutaneously with 107FLT3-ITD-positive MV4-11 human leukemia cells. When the tumor xenografts are well-established (10 days after implantation, mean tumor volumes of at least 100 mm3), animals are treated with either vehicle (10% DMSO, 20% PEG 400, 5% Tween 80 and 65% water) or CCT241736 administered orally at two doses, 50 and 100 mg/kg (n = 5 per group). Dosing is twice daily for 7 days, and once daily for a further 4 days[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
参考文献
[1]. Bavetsias V, et al. Optimization of imidazo[4,5-b]pyridine-based kinase inhibitors: identification of a dual FLT3/Aurora kinase inhibitor as an orally bioavailable preclinical development candidate for the treatment of acute myeloid leukemia. J Med Chem. 2012 Oct 25;55(20):8721-34.