生物活性

• 靶点	Bromodomain EC50:10-19nM

• 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
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  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

• 动物研究
  剂量	Mice[1]: 20 mg/kg - 25 mg/kg (i.p.), 100 mg/kg (p.o.)
  给药途径	i.p., p.o.
  动物药代数据	Animal Mice[3] Dose 50 mg/kg Administration i.h. Cmax ~ 750 ng/ml (4 h)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02698189	AML Including AML de Novo and ... more >>AML Secondary to MDS DLBCL Collapse <<	Phase 1	Active, not recruiting	January 31, 2019	-
  NCT02259114	-	-	Completed	-	-
  NCT02259114	NUT Midline Carcinoma ... more >> Triple Negative Breast Cancer Non-small Cell Lung Cancer With Rearranged ALK Gene/Fusion Protein or KRAS Mutation Castrate-resistant Prostate Cancer CRPC Pancreatic Ductal Adenocarcinoma Collapse <<	Phase 1	Completed	-	-

• 更多
• 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.