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Chemical Structure| 202590-98-5 同义名 : MK-8628;OTX-015;(−)-OTX015;HY-15743
CAS号 : 202590-98-5
货号 : A146187
分子式 : C25H22ClN5O2S
纯度 : 99%+
分子量 : 491.993
MDL号 : MFCD26960949
存储条件：

粉末 Sealed in dry,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 50 mg/mL(101.63 mM)，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

IP 2% DMSO+2% Tween80+40% PEG300+water 8 mg/mL clear

PO 0.5% CMC-Na 40 mg/mL suspension

生物活性
靶点

  • BET

    BRDs, EC50:10-19 nM
描述 The Bromodomain and extra-terminal domain BET (bromodomain and extra-terminal domain) family is characterized by the presence of two tandem bromodomains and an extra-terminal domain. BET proteins can govern the assembly of histone acetylation-dependent chromatin complexes, thus regulating gene expression. OTX015 (MK-8628) was the first in class inhibitor to enter clinical trials in hematologic diseases with IC50 value from 92 to 112nM for BRD2, BRD3, and BRD4, respectivelyDevelopment of the BET bromodomain inhibitor OTX015 http://mct.aacrjournals.org/content/12/11_Supplement/C244.short. After treatment with OTX015, a series of gene reported to be frequently affected by BET inhibition has been quantified in U87MG cells. Transient increases can be seen after 4h exposure to 500nM OTX015 for both C-MYC and CDKN1A but returned to basal levels after 24h. SESN3, HEXIM-1, HIST2H2BE, and HIST1H2BK gene all increased significantly after 4 and 24h exposure to OTX015, while MTHFD1L levels were significantly decreased after 24h exposure. A distinct pattern was seen for HIST2H4A and HIST1H2BJ with the significant increase was seen after 4h reversed to a significant decrease after 24h[1]. OTX015 can inhibit the growth of a variety of human cancer cell lines and had GI50 values ranged from 60 to 200nM for most hematologic malignancies tested. Oral administration of OTX015 showed 79% TGI at 100mg/kg, qd, and 61% TGI at 10mg/kg, bid, in Ty82 BRD-NUT midline carcinoma tumor miceDevelopment of the BET bromodomain inhibitor OTX015 http://mct.aacrjournals.org/content/12/11_Supplement/C244.short. OTX015 also showed anti-proliferative activity in a large panel of cell lines derived from mature B-cell lymphoid tumors with median IC50 of 240nM, without significant differences among the different histotypes. OTX015 presented in-vitro synergism with several anti-cancer agents, especially with mTOR and BTK inhibitors[2].
作用机制 OTX015 may have competitive inhibition on BRD2, BRD3, and BRD4Development of the BET bromodomain inhibitor OTX015 http://mct.aacrjournals.org/content/12/11_Supplement/C244.short.
细胞研究
细胞系 浓度 检测类型 检测时间 活动说明 数据源
Rosetta2 DE3 cells Function assay 30 mins Displacement of FAM-labeled ZBA248 from BRD3 BD2 (306 to 417 amino acid residues) (unknown origin) expressed in Rosetta2 DE3 cells after 30 mins by fluorescence polarization assay, Ki=4 nM 26080064
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.03mL

0.41mL

0.20mL

10.16mL

2.03mL

1.02mL

20.33mL

4.07mL

2.03mL
参考文献

[1]Berenguer-Daizé C, Astorgues-Xerri L, et al. OTX015 (MK-8628), a novel BET inhibitor, displays in vitro and in vivo antitumor effects alone and in combination with conventional therapies in glioblastoma models. Int J Cancer. 2016 Nov 1;139(9):2047-55.

[2]Boi M, Gaudio E, et al. The BET Bromodomain Inhibitor OTX015 Affects Pathogenetic Pathways in Preclinical B-cell Tumor Models and Synergizes with Targeted Drugs. Clin Cancer Res. 2015 Apr 1;21(7):1628-38.

[3]Gaudio E, Tarantelli C, et al. Bromodomain inhibitor OTX015 (MK-8628) combined with targeted agents shows strong in vivo antitumor activity in lymphoma. Oncotarget. 2016 Sep 6;7(36):58142-58147.