生物活性

• 靶点	DOT1L Ki:80pM

• 描述EPZ-5676 is a potent and selective aminonucleoside inhibitor of DOT1L histone methyltransferase activity with residence time >24h and Ki value of 0.08nM, demonstrating 37,000-fold selectivity over all other methyltransferases tested. Treatment with EPZ-5676 at concentration ranging in 1-1000nM for 4 days dose-dependently inhibited H3K79 methylation in MV4-11 cells. Also a dose-dependent decrease of HOXA9 and MEIS1 transcription could be observed in MV4-11 cells post 6-day treatment. EPZ-5676 could selectively and potently inhibit the proliferation of MLL-rearranged cells, but not non-MLL-rearranged cells, at concentration >0.0412μM post 14 days with increased level of apoptosis. Administration of EPZ-5676 at dose of 70mg/kg, daily, i.v., for 21 days achieved a complete tumor regression in a rat xenograft model of MLL-rearranged leukemia. Inhibition of DOT1L through injection with 5mg/kg EPZ-5676 in knees caused osteoarthritis in mice and disrupted the molecular signature of healthy chondrocytes in vitro, due to the loss of the suppression of Wnt signalling by inhibiting the activity of SIRT1.
• 作用机制EPZ-5676 occupies the SAM binding pocket and induces conformational changes in DOT1L^[1].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  human MOLM13 cells	-	Proliferation assay	-	Antiproliferative activity against human MOLM13 cells containing MLL-AF9, EC50=4 nM	23879463
  human MV4-11 cells	-	Function assay	4 days	Inhibition of DOT1L in human MV4-11 cells expressing MLL-AF4 assessed as reduction of H3K79me2 level after 4 days by ELISA method	25406853
  human MV4-11 cells	-	Proliferation assay	-	Antiproliferative activity against human MV4-11 cells containing MLL-AF4, EC50=4 nM	23879463

• 更多

• 动物研究
  剂量	Rat[1] (i.v.): min = 20 mg/kg, max = 70 mg/kg
  给药途径	i.v.
  动物药代数据	Animal Nude mice[1] Rats[1] Dose 20 mg/kg 1 mg/kg Administration i.p. i.v. bolus Cmax 4.93 μM 2.04 ± 0.23 μM·h T1/2 5.22 h 3.73 ± 1.03 h Vdss 1.66 ± 0.42 L/h/kg AUC0→t 3.69 μM·h 0.43 ± 0.03 μM·h F 0.47 AUC0-inf 3.69 μM·h 0.44 ± 0.03 μM·h Tmax 0.083 h 0.05 h CL 4.07 ± 0.32 L/h/kg MRT 0.84 h 0.41 ± 0.10 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
  NCT03724084	Acute Myeloid Leukemia ... more >> KMT2A Gene Rearrangement Collapse <<	Phase 1 Phase 2	Not yet recruiting	June 30, 2019	-
  NCT01684150	Acute Myeloid Leukemia ... more >> Acute Lymphoblastic Leukemia Myelodysplastic Syndrome Myeloproliferative Disorders Collapse <<	Phase 1	Completed	-	United States, Arizona ... more >> Mayo Clinic Scottsdale-Phoenix Scottsdale, Arizona, United States, 85259 United States, Illinois Northwestern University Chicago, Illinois, United States, 60611 United States, New York Memorial Sloan Kettering Cancer Center New York, New York, United States, 10065 United States, North Carolina Duke University Health System Durham, North Carolina, United States, 27710 United States, Tennessee Sarah Cannon Research Institute Nashville, Tennessee, United States, 37203 United States, Texas UT MD Anderson Cancer Houston, Texas, United States, 77030 Germany Universitätsklinikum Ulm Ulm, Germany, 89081 Netherlands Erasmus University Medical Center Rotterdam, Netherlands Collapse <<
  NCT02141828	Leukemia Acut... more >>e Myeloid Leukemia Acute Lymphocytic Leukemia Acute Leukemias Collapse <<	Phase 1	Completed	-	United States, California ... more >> Childrens Hospital Los Angeles Los Angeles, California, United States, 90027 University of California San Francisco Medical Center-Parnassus San Francisco, California, United States, 94143 United States, Colorado Children's Hospital Colorado Aurora, Colorado, United States, 80045 United States, Georgia Emory Children's Healthcare of Atlanta Atlanta, Georgia, United States, 30322 United States, Maryland Johns Hopkins University Baltimore, Maryland, United States, 21287 United States, Massachusetts Dana Farber Cancer Institute Boston, Massachusetts, United States, 02215 United States, New York Memorial Sloan Kettering Cancer Center New York, New York, United States, 10065 United States, Ohio Cincinnati Children's Hospital Medical Center Cincinnati, Ohio, United States, 45229 Canada, Ontario The Hospital for Sick Kids Toronto, Ontario, Canada Collapse <<

• 参考文献

• [1] Daigle SR, Olhava EJ, et al. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood. 2013 Aug 8;122(6):1017-25.

  [2] Monteagudo S, Cornelis FMF, et al. DOT1L safeguards cartilage homeostasis and protects against osteoarthritis. Nat Commun. 2017 Jun 19;8:15889.