N-(2H-1,3-benzodioxol-5-ylmethyl)-4-{8-oxa-3,5-diazatricyclo[7.4.0.0^{2,7}]trideca-1(13),2,4,6,9,11-hexaen-6-yl}piperazine-1-carbothioamide

• ChemBase编号: 72590
• 分子式: C23H21N5O3S
• 平均质量: 447.50954
• 单一同位素质量: 447.13651056
• SMILES: c1ccc2c(c1)c1c(o2)c(ncn1)N1CCN(CC1)C(=S)NCc1ccc2c(c1)OCO2
• Canonical SMILES: S=C(N1CCN(CC1)c1ncnc2c1oc1c2cccc1)NCc1ccc2c(c1)OCO2
• InChI: InChI=1S/C23H21N5O3S/c32-23(24-12-15-5-6-18-19(11-15)30-14-29-18)28-9-7-27(8-10-28)22-21-20(25-13-26-22)16-3-1-2-4-17(16)31-21/h1-6,11,13H,7-10,12,14H2,(H,24,32)
• InChIKey: FOFDIMHVKGYHRU-UHFFFAOYSA-N

名称和登记号

名称

• IUPAC标准名: N-(2H-1,3-benzodioxol-5-ylmethyl)-4-{8-oxa-3,5-diazatricyclo[7.4.0.0^{2,7}]trideca-1(13),2,4,6,9,11-hexaen-6-yl}piperazine-1-carbothioamide
• IUPAC传统名: N-(2H-1,3-benzodioxol-5-ylmethyl)-4-{8-oxa-3,5-diazatricyclo[7.4.0.0^{2,7}]trideca-1(13),2,4,6,9,11-hexaen-6-yl}piperazine-1-carbothioamide
• 别名: MP-470

登记号

• CAS号: 850879-09-3
• PubChem SID: 162037515
• PubChem CID: 11282283

理论计算性质

• Acid pKa: 14.11097
• 质子受体: 5
• 质子供体: 1
• LogD (pH = 5.5): 3.5177732
• LogD (pH = 7.4): 3.5178049
• Log P: 3.5178092
• 摩尔折射率: 124.5263 cm^3
• 极化性: 49.67749 Å^3
• 极化表面积: 75.89 Å^2
• 可自由旋转的化学键: 3
• 里宾斯基五规则: true

分子性质

理化性质

• 溶解度: DMSO

安全信息

• 保存条件: -20°C

药理学性质

• 作用靶点: c-Kit; c-Met; Flt; PDGFR

产品相关信息

• 成盐信息: Free Base

详细说明

Selleck Chemicals - S1244

Research Area

• Description: Cancer

Biological Activity

• Description: MP-470 (Amuvatinib) is a potent and multi-targeted inhibitor of c-Kit^D816H, PDGFα^V561D and Flt3^D835Y with IC50 of 10 nM, 40 nM and 81 nM, respectively.
• Targets: c-Kit^D816H; PDGFα^V561D; Flt3^D835Y
• IC50: 10 nM; 40 nM; 81 nM ^[1]
• In Vitro: The hydrochloride salt of MP-470 also inhibits several mutants of c-Kit, including c-Kit^D816V, c-Kit^D816H, c-Kit^V560G, and c-Kit^V654A, as well as a Flt3 mutant (Flt3^D835Y) and two PDGFα mutants (PDGFα^V561D and PDGFα^D842V), with IC50 of 10 nM to 8.4 μM. MP-470 hydrochloride potently inhibits the proliferation of OVCAR-3, A549, NCI-H647, DMS-153, and DMS-114 cells, with IC50 of 0.9 μM–7.86 μM. ^[1] MP-470 also inhibits c-Kit and PDGFα, with IC50 values of 31 μM and 27 μM, respectively. MP-470 demonstrates potent cytotoxicity against MiaPaCa-2, PANC-1, and GIST882 cells, with IC50 of 1.6 μM to 3.0 μM. MP-470 also binds to and inhibits several c-Kit mutants, including c-Kit^K642E, c-Kit^D816V, and c-Kit^K642E/D816V. ^[2] In MDA-MB-231 cells, MP-470 (1 μM) inhibits tyrosine phosphorylation of AXL. ^[3] In LNCaP and PC-3, but not DU145 cells, MP-470 exhibits cytotoxicity with IC50 of 4 μM and 8 μM, respectively, and induces apoptosis at 10 μM. In LNCaP cells, MP-470 (10 μM) elicits G1 arrest and decreases phosphorylation of Akt and ERK1/2. ^[4] In SF767 cells, MP-470 (10 μM) inhibits c-Met phosphorylation and sensitizes cells to radiation. In combination with radiation, MP-470 (10 μM) inhibits glycogen synthase kinase (GSK)3β activity, induces apoptosis, and disrupts the repair of dsDNA breaks probably through suppression of Rad51. ^[5]^[6]
• In Vivo: In mice xenograft models of HT-29, A549, and SB-CL2 cells, MP-470 (10 mg/kg–75 mg/kg via i.p. or 50 mg/kg–200 mg/kg via p.o.) inhibits tumor growth. ^[1]In mice bearing LNCaP xenograft, MP-470 (20 mg/kg) combined with Erlotinib significantly induces tumor growth inhibition (TGI). ^[4]
• Clinical Trials: MP-470 is currently under investigation in a Phase II clinical trial for small cell lung carcinoma.

Protocol

• Protocol: Kinase Assay ^[2]
• Kinase inhibition assay of c-Kit and PDGFα: For the testing of inhibitory activity against c-Kit and PDGFα, enzymes are incubated with varying concentrations of MP-470 and radiolabeled γ-^32P-ATP. After 30 min, the reaction mixtures are electrophoresed on an acrylamide gel and autophosphorylation, quantitated by the amount of radioactivity incorporated into the enzyme, is assayed.
• Protocol: Cell Assay ^[2]
• Cell Lines: MiaPaCa-2, PANC-1, and GIST882 cells
• Concentrations: 0–30 μM, dissolved in DMSO
• Incubation Time: 96 hours
• Methods: Cells are plated at a density of 2 × 10^3 to 1 × 10^4 cells per well in 100 μL medium on day 0 in 96-well Falcon microtitier plates. On day 1, ten μL of serial dilutions of MP-470 are added to the plates in quadruplicates. After incubation for 4 days, the cells are fixed with 10% Trichloroacetic acid solution. Subsequently, they are labeled with 0.04% Sulforhodamine B (SRB) in 1% acetic acid. After multiple washes to remove the excess dye, 100 μL of 50 mM Tris solution is added to each well in order to dissolve the dye. The absorbance of each well is read on a plate reader at 570 nm. Date are expressed as the percentage of survival of control calculated from the absorbance corrected for background absorbance. The surviving percent of cells is determined by dividing the mean absorbance values of the monoclonal antibody by mean absorbance values of the control and multiplying by 100.
• Protocol: Animal Study ^[1]
• Animal Models: Mice (athymic nude) xenograft models of HT-29, A549, and SB-CL2 cells
• Formulation: Dissolved in corn oil for p.o.;Dissolved in TV-10 (60% propylene glycol, 30% PEG300, 10% water, and 150 mg/mL 2-hydroxypropyl-β-cyclodextrin) or TV-10 (5% ethanol, 40% glycerol, 55% water, and 300 mg/mL cyclodextrin) for i.p.
• Doses: 10 mg/kg–75 mg/kg (i.p.) or 50 mg/kg–200 mg/kg (p.o.)
• Administration: Oral gavage (qd5 × 3 weeks) or intraperitoneal injection (qd5 × 2 weeks)

References

• References: [1] Bearss DJ, et al. US Patent, US/2008/0226747.
• References: [2] Hurley LH, et al. World Patent, WO/2005/037825.
• References: [3] Mahadevan D, et al. Oncogene, 2007, 26(27), 3909-3919.
• References: [4] Qi W, et al. BMC Cancer, 2009, 9, 142.
• References: [5] Welsh JW, et al. Radiat Oncol, 2009, 4, 69.
• References: [6] Zhao H, et al. Radiother Oncol, 2011, 101(1), 59-65.

参考文献

• Bearss DJ, et al. US Patent, US/2008/0226747.
• Hurley LH, et al. World Patent, WO/2005/037825.
• Mahadevan D, et al. Oncogene, 2007, 26(27), 3909-3919.
• Qi W, et al. BMC Cancer, 2009, 9, 142.
• Welsh JW, et al. Radiat Oncol, 2009, 4, 69.
• Zhao H, et al. Radiother Oncol, 2011, 101(1), 59-65.