[(1R)-1-{2-[(2,5-dichlorophenyl)formamido]acetamido}-3-methylbutyl]boronic acid

• ChemBase编号: 72877
• 分子式: C14H19BCl2N2O4
• 平均质量: 361.02866
• 单一同位素质量: 360.08149286
• SMILES: c1cc(cc(c1Cl)C(=O)NCC(=O)N[C@H](B(O)O)CC(C)C)Cl
• Canonical SMILES: OB([C@@H](NC(=O)CNC(=O)c1cc(Cl)ccc1Cl)CC(C)C)O
• InChI: InChI=1S/C14H19BCl2N2O4/c1-8(2)5-12(15(22)23)19-13(20)7-18-14(21)10-6-9(16)3-4-11(10)17/h3-4,6,8,12,22-23H,5,7H2,1-2H3,(H,18,21)(H,19,20)/t12-/m0/s1
• InChIKey: MXAYKZJJDUDWDS-LBPRGKRZSA-N

名称和登记号

名称

• IUPAC标准名: [(1R)-1-{2-[(2,5-dichlorophenyl)formamido]acetamido}-3-methylbutyl]boronic acid
• IUPAC传统名: (1R)-1-{2-[(2,5-dichlorophenyl)formamido]acetamido}-3-methylbutylboronic acid
• 别名: MLN2238

登记号

• CAS号: 1072833-77-2
• PubChem SID: 162037798
• PubChem CID: 25183872

理论计算性质

• Acid pKa: 12.108838
• 质子受体: 4
• 质子供体: 4
• LogD (pH = 5.5): 2.5677
• LogD (pH = 7.4): 2.567692
• Log P: 2.5677
• 摩尔折射率: 84.5563 cm^3
• 极化性: 34.363117 Å^3
• 极化表面积: 98.66 Å^2
• 可自由旋转的化学键: 7
• 里宾斯基五规则: true

分子性质

安全信息

• 保存条件: -20°C

药理学性质

• 作用靶点: Proteasome

产品相关信息

• 成盐信息: Free Base

详细说明

Selleck Chemicals - S2180

Research Area

• Description: Cancer

Biological Activity

• Description: MLN2238 inhibits the chymotrypsin-like proteolytic (β5) site of the 20S proteasome with IC50 and K_i of 3.4 nM and 0.93 nM, respectively.
• Targets: 20S proteasome
• IC50: 3.4 nM (IC50）, 0.93 nM（K_i) ^[1]
• In Vitro: At higher concentrations, MLN2238 also inhibits the caspase-like (β1) and trypsin-like (β2) proteolytic sites with IC50 of 31nM and 3.5uM, respectively. MLN2238 inhibits Calu-6 cell with IC50 of 9.7 nM. MLN2238 is a selective, potent, and reversible inhibitor of the proteasome in tumor cells. MLN2238 shows time-dependent reversible proteasome inhibition. Both MLN2238 and Bortezomib shows time-dependent reversible proteasome inhibition; however, the proteasome dissociation half-life for MLN2238 is determined to be ～6-fold faster than that of Bortezomib (18 and 110 minutes, respectively). MLN2238 dissociates more rapidly from the proteasome than Bortezomib, consistent with faster recovery of proteasome activity observed in the Proteasome-Glo assay. MLN2238 has a greater overall tumor pharmacodynamic effect than Bortezomib as assessed by 20S inhibition. ^[1]MLN2238 is the biologically active form of MLN9708. ^[2]
• In Vivo: MLN2238 induces a greater pharmacodynamic response than Bortezomib in xenograft tumors. MLN2238 shows greater maximum and sustained tumor proteasome inhibition compared with Bortezomib in xenograft models. These results confirm that the improved tumor exposure seen with MLN2238 translates into an improved tumor pharmacodynamic response both at the level of and downstream from the proteasome. MLN2238 shows antitumor activity in the CWR22 xenograft model. MLN2238 shows greater tumor pharmacodynamic responses in WSU-DLCL2 xenografts compared with Bortezomib. Similarly, Bortezomib treatment only led to a minor increase in GADD34 levels in WSU-DLCL2 xenograft tumors, whereas MLN2238 strongly induces its expression. ^[1] MLN2238 has an improved pharmacodynamic profile and antitumor activity compared with Bortezomib in both OCI-Ly10 and PHTX22L models. ^[2]
• Clinical Trials: MLN2238 is current under Phase II clinical trial in patients with relapsed multiple myeloma not refractory to bortezomib.
• Features: MLN2238 is the first-in-class proteasome inhibitor, has improved pharmacokinetics (PK), pharmacodynamics(PD), and antitumor activity in preclinical studies.

Protocol

• Protocol: Kinase Assay ^[1]
• Kinase assay: Calu-6 cells are cultured in MEM containing 10% fetal bovine serum and 1% penicillin/streptomycin and plated 1 day before the start of the experiment at 1 × 10^4 cells per well in a 384-well plate. Proteasome activity is assessed by monitoring hydrolysis of the chymotrypsin-like substrate Suc-LLVY-aminoluciferin in the presence of luciferase using the Proteasome-Glo assay reagents according to the manufacturer's instructions. Luminescence is measured using a LEADseeker instrument.
• Protocol: Cell Assay ^[1]
• Cell Lines: Calu-6 cells
• Concentrations: ~10 nM
• Incubation Time: 1 hour or 30 minutes
• Methods: Calu-6 cells are cultured in MEM containing 10% FBS and 1% penicillin/streptomycin and plated 1 day before the start of the experiment at 1 × 10^4 cells per well in a 384-well plate. For IC50 determinations, cells are treated with varying concentrations of Bortezomib or MLN2238 in DMSO (0.5% final, v/v) for 1 hour at 37 °C. For reversibility experiments, cells are treated with either 1 μM Bortezomib or MLN2238 for 30 minutes at 37 °C and then washed thrice in medium to remove the Bortezomib or MLN2238. Cells are incubated for an additional 4 hours at 37 °C, after which the medium is removed and replaced with fresh medium.
• Protocol: Animal Study ^[2]
• Animal Models: CB-17 SCID mice are subcutaneously inoculated with MM.1S cells
• Formulation: Dissolved in 5% 2-hydroxypropyl-β-cyclodextrin
• Doses: 11 mg/kg
• Administration: Twice weekly for 3 weeks (i.v.)

References

• References: [1] Kupperman E, et al. Cancer Res, 2010, 70(5), 1970-80
• References: [2] Lee EC, et al. Clin Cancer Res, 2011, 17(23), 7313-23.

参考文献

• Kupperman E, et al. Cancer Res, 2010, 70(5), 1970-80
• Lee EC, et al. Clin Cancer Res, 2011, 17(23), 7313-23.