生物活性

• 靶点

  ATM Ki:34nM

  ATR Ki:0.2nM

  DNA-PK Ki:4μM

  mTOR Ki:1μM

• 描述ATR/ATM kinases can phosphorylate a broad and overlapping catalogue of several thousand substrates in DNA damage signaling. The kinase activity of ATR, activated by single-stranded DNA (ssDNA) coated with replication protein A (RPA), is increased at damaged replication forks and resected DNA double-strand breaks (DSBs). VE-822 is a close analog of VE-821, possessing a marked potency against ATR with Ki value < 0.2nM, as well as cell IC50 value of 19nM. The cell study showed that VE-822 can attenuate ATR signaling pathway and reduce survival in tumor cells in response to XRT and gemcitabine. Treatment with VE-822 (80nM) reduced pChk1-Ser345, as the major marker for ATR inhibition, after gemcitabine (100 nM), XRT (6 Gy) or both in MiaPaCa-2 and PSN-1 cells or in vivo study, alone with dramatically reduced survival of these two tumor cells (but not in normal cells). 1h pre-treatment with 80nM VE-822 increased XRT-induced residual γH2AX and 53BP1 foci, whereas no effect on VE-822 alone, suggesting the enhancement of residual DNA damage by VE-822 in vitro. Oral administration with VE-822 at dose of 60mg/kg enhanced the therapeutic efficacy of radiation (XRT) in MiaPaCa-2 and PSN-1 xenograft models, as well as enhanced tumor response in combination with XRT and gemcitabine in PSN-1 xenografts^[1].
• 作用机制VE-822 is a close analog of VE-821, which acts as an ATP-competitive inhibitor of ATR.^[1]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  HCK1T-HPV16	0.5 nM	Function Assay	24 h	increases the levels of E1	25717108
  HCK1T-HPV16	0.5 nM	Function Assay	24 h	enhances E1-dependent replication of the HPV16 genome	25717108

• 动物研究
  剂量	Mice[1] (p.o.): 60 mg/kg
  给药途径	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
  NCT03641313	Clinical Stage III Gastric Can... more >>cer AJCC v8 Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8 Clinical Stage IV Gastric Cancer AJCC v8 Clinical Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8 Clinical Stage IVA Gastric Cancer AJCC v8 Clinical Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8 Clinical Stage IVB Gastric Cancer AJCC v8 Clinical Stage IVB Gastroesophageal Junction Adenocarcinoma AJCC v8 Metastatic Gastric Adenocarcinoma Metastatic Gastroesophageal Junction Adenocarcinoma Pathologic Stage III Gastric Cancer AJCC v8 Pathologic Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage IIIA Gastric Cancer AJCC v8 Pathologic Stage IIIA Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage IIIB Gastric Cancer AJCC v8 Pathologic Stage IIIB Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage IIIC Gastric Cancer AJCC v8 Pathologic Stage IV Gastric Cancer AJCC v8 Pathologic Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage IVB Gastroesophageal Junction Adenocarcinoma AJCC v8 Postneoadjuvant Therapy Stage III Gastric Cancer AJCC v8 Postneoadjuvant Therapy Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8 Postneoadjuvant Therapy Stage IIIA Gastroesophageal Junction Adenocarcinoma AJCC v8 Postneoadjuvant Therapy Stage IIIB Gastroesophageal Junction Adenocarcinoma AJCC v8 Postneoadjuvant Therapy Stage IV Gastric Cancer AJCC v8 Postneoadjuvant Therapy Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8 Postneoadjuvant Therapy Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8 Postneoadjuvant Therapy Stage IVB Gastroesophageal Junction Adenocarcinoma AJCC v8 TP53 Gene Mutation Unresectable Gastroesophageal Junction Adenocarcinoma Collapse <<	Phase 2	Not yet recruiting	May 31, 2020	-
  NCT02567422	Head and Neck Squamous Cell Ca... more >>rcinoma Human Papillomavirus Negative Stage III Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma AJCC v6 and v7 Stage III Oropharyngeal Squamous Cell Carcinoma AJCC v7 Stage IV Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma AJCC v7 Stage IV Oropharyngeal Squamous Cell Carcinoma AJCC v7 Stage IVA Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma AJCC v7 Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7 Stage IVB Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma AJCC v7 Stage IVB Oropharyngeal Squamous Cell Carcinoma AJCC v7 Stage IVC Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma AJCC v7 Stage IVC Oropharyngeal Squamous Cell Carcinoma AJCC v7 Collapse <<	Phase 1	Recruiting	-	United States, California ... more >> City of Hope Comprehensive Cancer Center Recruiting Duarte, California, United States, 91010 Contact: Site Public Contact    800-826-4673    becomingapatient@coh.org    Principal Investigator: Erminia Massarelli          University of California Davis Comprehensive Cancer Center Recruiting Sacramento, California, United States, 95817 Contact: Site Public Contact    916-734-3089       Principal Investigator: Jonathan W. Riess          United States, Connecticut Smilow Cancer Center/Yale-New Haven Hospital Recruiting New Haven, Connecticut, United States, 06510 Contact: Site Public Contact    203-785-5702    canceranswers@yale.edu    Principal Investigator: Barbara A. Burtness          Yale University Recruiting New Haven, Connecticut, United States, 06520 Contact: Site Public Contact    203-785-5702    canceranswers@yale.edu    Principal Investigator: Barbara A. Burtness          United States, Georgia Emory University Hospital Midtown Recruiting Atlanta, Georgia, United States, 30308 Contact: Site Public Contact    888-946-7447       Principal Investigator: Conor E. Steuer          Emory University Hospital/Winship Cancer Institute Recruiting Atlanta, Georgia, United States, 30322 Contact: Site Public Contact    404-778-1868       Principal Investigator: Conor E. Steuer          United States, Kentucky University of Kentucky/Markey Cancer Center Recruiting Lexington, Kentucky, United States, 40536 Contact: Site Public Contact    859-257-3379       Principal Investigator: Susanne M. Arnold          United States, Maryland Johns Hopkins University/Sidney Kimmel Cancer Center Suspended Baltimore, Maryland, United States, 21287 United States, Ohio Case Western Reserve University Suspended Cleveland, Ohio, United States, 44106 Ohio State University Comprehensive Cancer Center Recruiting Columbus, Ohio, United States, 43210 Contact: Site Public Contact    800-293-5066    Jamesline@osumc.edu    Principal Investigator: Darrion L. Mitchell          United States, Virginia University of Virginia Cancer Center Recruiting Charlottesville, Virginia, United States, 22908 Contact: Site Public Contact    434-243-6303    PAS9E@virginia.edu    Principal Investigator: Varinder Kaur          United States, Wisconsin University of Wisconsin Hospital and Clinics Recruiting Madison, Wisconsin, United States, 53792 Contact: Site Public Contact    800-622-8922       Principal Investigator: Justine Yang-Bruce Collapse <<
  NCT02595892	Ovarian Serous Tumor ... more >> Recurrent Fallopian Tube Carcinoma Recurrent Ovarian Carcinoma Recurrent Primary Peritoneal Carcinoma Collapse <<	Phase 2	Recruiting	-	United States, Arizona ... more >> Mayo Clinic Hospital Recruiting Phoenix, Arizona, United States, 85054 Contact: Site Public Contact    855-776-0015       Principal Investigator: Andrea E. Wahner Hendrickson          Mayo Clinic in Arizona Recruiting Scottsdale, Arizona, United States, 85259 Contact: Site Public Contact    855-776-0015       Principal Investigator: Andrea E. Wahner Hendrickson          United States, California UC San Diego Moores Cancer Center Recruiting La Jolla, California, United States, 92093 Contact: Site Public Contact    858-822-5354    cancercto@ucsd.edu    Principal Investigator: Michael T. McHale          University of California San Diego Recruiting San Diego, California, United States, 92103 Contact: Site Public Contact    858-822-5354    cancercto@ucsd.edu    Principal Investigator: Michael T. McHale          United States, Florida Mayo Clinic in Florida Recruiting Jacksonville, Florida, United States, 32224-9980 Contact: Site Public Contact    855-776-0015       Principal Investigator: Andrea E. Wahner Hendrickson          United States, Massachusetts Massachusetts General Hospital Cancer Center Recruiting Boston, Massachusetts, United States, 02114 Contact: Site Public Contact    877-726-5130       Principal Investigator: Panagiotis A. Konstantinopoulos          Brigham and Women's Hospital Recruiting Boston, Massachusetts, United States, 02115 Contact: Site Public Contact    888-823-5923    ctsucontact@westat.com    Principal Investigator: Panagiotis A. Konstantinopoulos          Beth Israel Deaconess Medical Center Recruiting Boston, Massachusetts, United States, 02215 Contact: Site Public Contact    617-667-9925       Principal Investigator: Panagiotis A. Konstantinopoulos          Dana-Farber Cancer Institute Recruiting Boston, Massachusetts, United States, 02215 Contact: Site Public Contact    877-442-3324       Principal Investigator: Panagiotis A. Konstantinopoulos          United States, Michigan Wayne State University/Karmanos Cancer Institute Recruiting Detroit, Michigan, United States, 48201 Contact: Site Public Contact    313-576-9790    ctoadmin@karmanos.org    Principal Investigator: Ira S. Winer          United States, Minnesota Mayo Clinic Recruiting Rochester, Minnesota, United States, 55905 Contact: Site Public Contact    855-776-0015       Principal Investigator: Andrea E. Wahner Hendrickson          United States, Pennsylvania Thomas Jefferson University Hospital Recruiting Philadelphia, Pennsylvania, United States, 19107 Contact: Site Public Contact    215-955-6084       Principal Investigator: Russell J. Schilder          University of Pittsburgh Cancer Institute (UPCI) Recruiting Pittsburgh, Pennsylvania, United States, 15232 Contact: Site Public Contact    412-647-8073       Principal Investigator: Alexander B. Olawaiye          United States, Tennessee Vanderbilt University/Ingram Cancer Center Recruiting Nashville, Tennessee, United States, 37232 Contact: Site Public Contact    800-811-8480       Principal Investigator: Marta A. Crispens          United States, Texas M D Anderson Cancer Center Recruiting Houston, Texas, United States, 77030 Contact: Site Public Contact    877-312-3961       Principal Investigator: Siqing Fu          United States, Virginia University of Virginia Cancer Center Recruiting Charlottesville, Virginia, United States, 22908 Contact: Site Public Contact    434-243-6303    PAS9E@virginia.edu    Principal Investigator: Linda R. Duska          United States, Wisconsin University of Wisconsin Hospital and Clinics Recruiting Madison, Wisconsin, United States, 53792 Contact: Site Public Contact    800-622-8922       Principal Investigator: Lisa M. Barroilhet Collapse <<

• 更多
• 参考文献

• [1] Fokas E, Prevo R, et al. Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. Cell Death Dis. 2012 Dec 6;3:e441.

  [2] Josse R, Martin SE, et al. ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses. Cancer Res. 2014 Dec 1;74(23):6968-79.