货号：O3739

储存条件：粉末-20°C可保存3年；液体-80°C可保存12月。

产品描述

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.

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. 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.

作用机制

OTX015 may have competitive inhibition on BRD2, BRD3, and BRD4Development of the BET bromodomain inhibitor OTX015. 

产品信息