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MLN2238

产品号 S2180 公司名称 Selleck Chemicals
CAS号 1072833-77-2 公司网站 http://www.selleckchem.com
分子式 C14H19BCl2N2O4 电 话 (877) 796-6397
分子量 361.02866 传 真 (832) 582-8590
纯 度 电子邮件 sales@selleckchem.com
保 存 -20°C Chembase数据库ID: 72877

产品价格信息

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产品别名

标题
MLN2238
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

产品登记号

CAS号 1072833-77-2

产品性质

作用靶点 Proteasome
成盐信息 Free Base
保存条件 -20°C

产品详细信息

详细说明 (English)
Research Area
Description Cancer
Biological Activity
Description MLN2238 inhibits the chymotrypsin-like proteolytic (β5) site of the 20S proteasome with IC50 and Ki of 3.4 nM and 0.93 nM, respectively.
Targets 20S proteasome
IC50 3.4 nM (IC50), 0.93 nM(Ki) [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
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 × 104 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.
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 × 104 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.
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
[1] Kupperman E, et al. Cancer Res, 2010, 70(5), 1970-80
[2] Lee EC, et al. Clin Cancer Res, 2011, 17(23), 7313-23.