生物活性

• 描述The Bromodomain and Extra-Terminal Domain (BET) family of proteins is characterized by the presence of two tandem bromodomains and an extra-terminal domain. It can play a crucial role in regulating gene transcription through epigenetic interactions between bromodomains and acetylated histones. CPI-0610 is a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor with IC50 value of 39nM in a BRD4-BD1 TR-FRET assay. It effectively reduced the expression of downstream target MYC on RNA level in MV-4-11 cells with EC50 value of 180nM. Similarly, this downregulation of MYC could be also observed in vivo at dose of 15mg/kg, BID. Oral administration of CPI-0610 effectively inhibited MV-4-11 tumor growth in mouse xenograft at dose of 60mg/kg, QD or 30mg/kg, BID. Also, it synergized the tumor growth suppression of doxorubicin (2 mg/kg, IV, BIW) at dose of 10mg/kg, SC, BID. CPI-0610 treatment resulted in MM cytotoxicity at dose ranging in 200-1500nM post 72h in vitro by inducing G1 cell cycle arrest and caspase-dependent apoptosis. CPI-0610 significantly delayed tumor growth and increased the survival of MM-bearing SCID mice in a xenograft model at dose of 10mg/kg (dissolved in 0.5% (w/v) methylcellulose), SC, BID.
• 作用机制CPI-0610 could bind in the acetyl-lysine recognition site and make direct hydrogen-bonding interactions with Asn140 of the target protein.^[1]

• 动物研究
  剂量	Mice[1]: 30 mg/kg (p.o., s.c.); rat[1]: 1 mg/kg (i.v.), 5 mg/kg (p.o.)
  给药途径	p.o., s.c., i.v.
  动物药代数据	Animal Mice[1] Rats[1] Dogs[1] Dose 30 mg/kg 1 mg/kg (i.v.) 5 mg/kg (p.o.) 0.5 mg/kg (i.v.) 2.5 mg/kg (p.o.) Administration p.o. s.c. i.v. p.o. i.v. p.o. AUC0→inf 101 μM·h (p.o.) 49 μM·h (s.c.) 28 μM·h (p.o.) F 76% (p.o.) 45% (p.o.) T1/2 0.93 h (i.v.) 9 h (i.v.) Tmax 0.42 h (p.o.) 1.3 h (s.c.) 1.2 h (p.o.) 1.3 h (p.o.) AUC0-inf 9.1 μM·h (p.o.) CL 1.2 L/h/kg (i.v.) 0.11 L/h/kg (i.v.) Cmax 24 μM (p.o.) 8.4 μM (s.c.) 1.8 μM (p.o.) 2.9 μM (p.o.) Vss 1.3 L/kg (i.v.) 1.2 L/kg (i.v.)

• 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
  NCT02157636	Multiple Myeloma	Phase 1	Completed	-	-
  NCT02986919	Peripheral Nerve Tumors	Phase 2	Withdrawn(Lack of enrollment.)	-	United States, Texas ... more >> University of Texas Southwestern Medical Center Dallas, Texas, United States, 75390 Collapse <<
  NCT02158858	Myelofibrosis ... more >> Leukemia, Myelocytic, Acute Myelodysplastic/Myeloproliferative Neoplasm Myelodysplastic Syndrome (MDS) Collapse <<	Phase 1 Phase 2	Recruiting	March 2020	United States, California ... more >> UCLA Medical Center Recruiting Los Angeles, California, United States, 90095 Contact: Farzam Hariri       FHariri@mednet.ucla.edu    Principal Investigator: Gary Schiller, MD          United States, Indiana Horizon Oncology Center Recruiting Lafayette, Indiana, United States, 47905 Contact: Wael Harb, MD    765-446-5111    info@horizonbioadvance.com    Principal Investigator: Wael Harb, MD          United States, Massachusetts Massachusetts General Hospital Active, not recruiting Boston, Massachusetts, United States, 02114 United States, New York Icahn School of Medicine at Mount Sinai Recruiting New York, New York, United States, 10029 Contact: Frank Fabris    212-241-8999    frank.fabris@mssm.edu    Principal Investigator: Marina Kremyanskya, MD PhD          Columbia University Medical Centre Recruiting New York, New York, United States, 10032 Contact: Mackenzie Snead       mbs2173@cumc.columbia.edu    Principal Investigator: Mark Heaney          Memorial Sloan-Kettering Cancer Center Active, not recruiting New York, New York, United States, 10065 United States, Ohio Gabrail Cancer Center Recruiting Canton, Ohio, United States, 44718 Contact: Carrie Smith, RN       CSmith@GabrailCancerCenter.com    Principal Investigator: Nashat Gabrail, MD          United States, Pennsylvania University of Pennsylvania - Perelman Center for Advanced Medicine Active, not recruiting Philadelphia, Pennsylvania, United States, 19104 United States, Texas MD Anderson Cancer Center Recruiting Houston, Texas, United States, 77030 Contact: Kurt Schroeder, RN    713-563-2622    kdschroe@mdanderson.org    Principal Investigator: Prithviraj Bose, MD          Canada, Alberta University of Alberta Hospital Recruiting Edmonton, Alberta, Canada, T6G 2G3 Contact: Lori Rackel    780-407-1811    lori.rackel@albertahealthservices.ca    Principal Investigator: Elena Liew, MD          Canada, British Columbia St. Paul's Hospital Recruiting Vancouver, British Columbia, Canada, V6Z 2A5 Contact: Rachel Despotovic    604-875-5296    rachel.despotovic@vch.ca    Principal Investigator: Lynda Foltz, MD          Canada, Ontario Juravinski Cancer Centre Recruiting Hamilton, Ontario, Canada, L8V 5C2 Contact: Elisa Shore       elisa.shore@jcc.hhsc.ca    Principal Investigator: Brian Leber          Princess Margaret Cancer Centre Recruiting Toronto, Ontario, Canada, M5G 2M9 Contact: Sabina Naqvi    416-581-8619    sabina.naqvi@uhn.ca    Principal Investigator: Vikas Gupta, MD Collapse <<

• 更多
• 参考文献

• [1] Albrecht BK, Gehling VS, et al. Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Family as a Candidate for Human Clinical Trials. J Med Chem. 2016 Feb 25;59(4):1330-9.

  [2] Siu KT, Ramachandran J, et al. Preclinical activity of CPI-0610, a novel small-molecule bromodomain and extra-terminal protein inhibitor in the therapy of multiple myeloma. Leukemia. 2017 Aug;31(8):1760-1769.