生物活性

• 靶点	EZH2 Ki:2.5±0.5nM

• 描述EZH2 is the enzymatically active core subunit of the PRC2 complex, which methylates H3K27 and facilitates chromatin compaction and gene silencing. EPZ-6438 is a potent and selective inhibitor of EZH2 with Ki value of 2.5 ± 0.5 nM （measured by competition with SAM）, with selectivity >4,500-fold over 14 other HMTs, 35-fold over EZH1. Similar potency can be observed for EZH2 proteins bearing all known lymphoma change-of-function mutations. Treatment with EPZ-6438 (6 - 1100 nM) for 4 days caused specific concentration-dependent reductions in global H3K27Me3 levels in a panel of SMARCB1-deficient MRT cells and SMARCB1 wild-type control cells. And this specific inhibition on cellular H3K27 methylation led to selective apoptotic killing of SMARCB1 mutant MRT cells with IC50 values in the nanomolar range. EPZ-6438 (1 μM) treatment of G401 SMARCB1-deleted cells for up to 7 days strongly induced expression of CD133, DOCK4 and PTPRK (genes important for neuronal differentiation) and up-regulated cell cycle inhibitors CDKN1A, CDKN2A and tumor suppressor BIN1, all in a time-dependent manner, as well as down-regulated the expression of hedgehog pathway genes MYC and EZH2. Oral treatment of EPZ-6438 on dose of 125, 250 an 500 mg/kg, twice daily, for 21 days induced tumor regressions in SCID mice bearing s.c. G401 xenografts. Correlating with the antitumor activity, tumors that were harvested from subsets of mice from each group on day 21 showed strong inhibition of H3K27Me3223620515. Up to now, phase 2 studies of EPZ-6438 on treatment for Diffuse Large B-cell Lymphoma, Rhabdoid Tumors, Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma, Advanced Malignant Solid Neoplasm, etc., are recruiting (see https://clinicaltrials.gov/).
• 作用机制EPZ-6438 inhibits EZH2 in a manner competitive with the substrate S-adenosylmethionine (SAM) binding to EZH2.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  human HeLa cells	-	Function assay	72 h	Inhibition of EZH2 in human HeLa cells assessed as reduction in H3K27me3 levels incubated for 72 hrs by ELISA method, IC50=0.02 μM.	26189078

• 动物研究
  剂量	Mice[2] (s.c.): 125 mg/kg - 500 mg/kg; rat[3] (p.o.): 100 mg/kg - 1000 mg/kg
  给药途径	s.c., p.o.
  动物药代数据	Animal Mice[4] Dose 1 mg/kg (i.v.) 2 mg/kg (p.o.) Administration i.v. p.o. T1/2 1.6 h (i.v.) Vdss 1.2 L/kg (i.v.) CL 22 ml/min/kg (i.v.) F 20% (p.o.)

• 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
  NCT03155620	Advanced Malignant Solid Neopl... more >>asm Ann Arbor Stage III Childhood Non-Hodgkin Lymphoma Ann Arbor Stage IV Childhood Non-Hodgkin Lymphoma Childhood Langerhans Cell Histiocytosis Histiocytic Sarcoma Juvenile Xanthogranuloma Malignant Glioma Recurrent Central Nervous System Neoplasm Recurrent Childhood Ependymoma Recurrent Childhood Malignant Germ Cell Tumor Recurrent Childhood Medulloblastoma Recurrent Childhood Non-Hodgkin Lymphoma Recurrent Childhood Rhabdomyosarcoma Recurrent Childhood Soft Tissue Sarcoma Recurrent Ewing Sarcoma Recurrent Glioma Recurrent Hepatoblastoma Recurrent Langerhans Cell Histiocytosis Recurrent Malignant Solid Neoplasm Recurrent Neuroblastoma Recurrent Osteosarcoma Recurrent Peripheral Primitive Neuroectodermal Tumor Recurrent Rhabdoid Tumor Refractory Central Nervous System Neoplasm Refractory Childhood Malignant Germ Cell Tumor Refractory Ewing Sarcoma Refractory Glioma Refractory Hepatoblastoma Refractory Langerhans Cell Histiocytosis Refractory Malignant Solid Neoplasm Refractory Medulloblastoma Refractory Neuroblastoma Refractory Non-Hodgkin Lymphoma Refractory Osteosarcoma Refractory Peripheral Primitive Neuroectodermal Tumor Refractory Rhabdoid Tumor Refractory Rhabdomyosarcoma Rhabdoid Tumor Stage III Osteosarcoma AJCC v7 Stage III Soft Tissue Sarcoma AJCC v7 Stage IV Osteosarcoma AJCC v7 Stage IV Soft Tissue Sarcoma AJCC v7 Stage IVA Osteosarcoma AJCC v7 Stage IVB Osteosarcoma AJCC v7 Wilms Tumor Collapse <<	Phase 2	Recruiting	September 30, 2027	-
  NCT03009344	Relapsed or Refractory B-cell ... more >>Non-Hodgkin's Lymphoma Collapse <<	Phase 1	Active, not recruiting	November 2019	Japan ... more >> Eisai Trial Site Isehara, Kanagawa, Japan Eisai Trial Site Chuo-ku, Tokyo, Japan Collapse <<
  NCT03456726	Relapsed or Refractory B-cell ... more >>Non-Hodgkin's Lymphoma Collapse <<	Phase 2	Active, not recruiting	September 2020	Japan ... more >> 1004 Eisai Trial Site Nagoya, Aichi, Japan 1028 Eisai Trial Site Nagoya, Aichi, Japan 1019 Eisai Trial Site Ota, Gunma, Japan 1007 Eisai Trial Site Sapporo, Hokkaido, Japan 1018 Eisai Trial Site Kobe, Hyogo, Japan 1005 Eisai Trial Site Tsukuba, Ibaraki, Japan 1002 Eisai Trial Site Isehara, Kanagawa, Japan 1027 Eisai Trial Site Yokohama, Kanagawa, Japan 1020 Eisai Trial Site Sendai, Miyagi, Japan 1013 Eisai Trial Site Osakasayama, Osaka, Japan 1006 Eisai Trial Site Suita, Osaka, Japan 1026 Eisai Trial Site Suntou-gun, Shizuoka, Japan 1025 Eisai Trial Site Bunkyo-ku, Tokyo, Japan 1001 Eisai Trial Site Chuo-ku, Tokyo, Japan 1024 Eisai Trial Site Koto-ku, Tokyo, Japan 1016 Eisai Trial Site Minato-ku, Tokyo, Japan 1021 Eisai Trial Site Aomori, Japan 1010 Eisai Trial Site Chiba, Japan 1012 Eisai Trial Site Fukuoka, Japan 1015 Eisai Trial Site Fukuoka, Japan 1011 Eisai Trial Site Hiroshima, Japan 1023 Eisai Trial Site Kumamoto, Japan 1003 Eisai Trial Site Kyoto, Japan 1008 Eisai Trial Site Kyoto, Japan 1022 Eisai Trial Site Nagasaki, Japan 1009 Eisai Trial Site Okayama, Japan 1014 Eisai Trial Site Osaka, Japan 1017 Eisai Trial Site Yamagata, Japan Collapse <<

• 更多
• 参考文献

• [1] Knutson SK, Warholic NM, et al. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc Natl Acad Sci U S A. 2013 May 7;110(19):7922-7.

  [2] Knutson SK, Kawano S, et al. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol Cancer Ther. 2014 Apr;13(4):842-54.

  [3] Huang Y, Zhang J, et al. Discovery of First-in-Class, Potent, and Orally Bioavailable Embryonic Ectoderm Development (EED) Inhibitor with Robust Anticancer Efficacy. J Med Chem. 2017 Mar 23;60(6):2215-2226.