生物活性

• 靶点

  Bcl-2 Ki:1nM

  Bcl-w Ki:1nM

  Bcl-xL Ki:0.5nM

• 描述The B-cell lymphoma 2 (Bcl-2) family of proteins is composed of both antiapoptotic members, such as Bcl-2, Bcl-xL as well as Bcl-w, and proapoptotic members. Up-regulation of the pro-survival Bcl-2 family proteins is one of the primary means for cancer cells to evade apoptosis. ABT-263, advanced based on ABT-737, is a potent and orally bioavailable Bcl-2 family inhibitor (Bcl-xL Ki≤0.5nM,Bcl-2 Ki≤1nM,Bcl-w Ki≤1nM, FPA assay; Bcl-xL Ki=0.4nM, TR-FRET assay; Mcl-1 IC50=550±40nM, A1 IC50=354±63nM,reported). It can disrupt Bcl-xL/Bcl-xS interaction, as well as activates Bax and cytochrome c (Cyto c) release. ABT-263 exhibited single-agent activity in SCLC and hematologic malignancies but not in the majority of other tumor types. Oral dosing of ABT-263 results in the regression of SCLC and ALL xenograft tumors in vivo. Also it enhances the activity of chemotherapeutic agents^[1]. The clinical trials of ABT-263 on relapsed/refractory CLL, platinum-resistant, refractory ovarian cancer, etc. are undergoing^[2].
• 作用机制ABT-263 directly binds Bcl-2 as well as Bcl-xL and blocks their ability to bind to BIM.^[3]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  5637	-	Growth Inhibition Assay	-	IC50=3.61103 μM	SANGER
  697	-	Growth Inhibition Assay	-	IC50=0.10839 μM	SANGER
  769-P	-	Growth Inhibition Assay	-	IC50=3.8951 μM	SANGER

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• 动物研究
  剂量	Mice: min = 50 mg/kg[4], max = 100 mg/kg[5]
  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
  NCT01423539	Diffuse Large B-Cell Lymphoma	Phase 2	Withdrawn(The NAVIGATE study h... more >>as been terminated due to non-safety related reasons.) Collapse <<	February 2014	United States, California ... more >> Fountain Valley, California, United States, 92708 United States, Florida Hudson, Florida, United States, 34667 United States, Georgia Lawrenceville, Georgia, United States, 30045 United States, Illinois Centralia, Illinois, United States, 62801 Harvey, Illinois, United States, 60426 United States, Indiana Terre Haute, Indiana, United States, 47802 United States, Kentucky Hazard, Kentucky, United States, 41701 Paducah, Kentucky, United States, 42003 United States, Maryland Rockville, Maryland, United States, 20850 United States, Missouri Jefferson City, Missouri, United States, 65109 United States, Montana Great Falls, Montana, United States, 59405 United States, Ohio Newark, Ohio, United States, 43055 United States, Tennessee Nashville, Tennessee, United States, 37203 Collapse <<
  NCT01053520	Healthy Female Subjects	Phase 1	Completed	-	United States, Illinois ... more >> Site Reference ID/Investigator# 23602 Waukegan, Illinois, United States, 60085 Collapse <<
  NCT01989585	BRAF V600E Mutation Present ... more >> BRAF V600K Mutation Present Metastatic Melanoma Solid Neoplasm Stage III Cutaneous Melanoma AJCC v7 Stage IIIA Cutaneous Melanoma AJCC v7 Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Stage IV Cutaneous Melanoma AJCC v6 and v7 Collapse <<	Phase 1 Phase 2	Recruiting	-	United States, California ... more >> University of California Davis Comprehensive Cancer Center Suspended Sacramento, California, United States, 95817 United States, Massachusetts Massachusetts General Hospital Cancer Center Withdrawn Boston, Massachusetts, United States, 02114 United States, Missouri Siteman Cancer Center at West County Hospital Suspended Creve Coeur, Missouri, United States, 63141 Washington University School of Medicine Suspended Saint Louis, Missouri, United States, 63110 Siteman Cancer Center-South County Suspended Saint Louis, Missouri, United States, 63129 Siteman Cancer Center at Christian Hospital Suspended Saint Louis, Missouri, United States, 63136 Siteman Cancer Center at Saint Peters Hospital Suspended Saint Peters, Missouri, United States, 63376 United States, New Jersey Rutgers Cancer Institute of New Jersey Recruiting New Brunswick, New Jersey, United States, 08903 Contact: Site Public Contact    732-235-8675       Principal Investigator: Janice M. Mehnert          United States, North Carolina Duke University Medical Center Recruiting Durham, North Carolina, United States, 27710 Contact: Site Public Contact    888-275-3853       Principal Investigator: James L. Abbruzzese          United States, Ohio Ohio State University Comprehensive Cancer Center Recruiting Columbus, Ohio, United States, 43210 Contact: Site Public Contact    800-293-5066    Jamesline@osumc.edu    Principal Investigator: Kari L. Kendra          United States, Texas M D Anderson Cancer Center Recruiting Houston, Texas, United States, 77030 Contact: Site Public Contact    877-312-3961       Principal Investigator: Michael A. Davies Collapse <<

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• 参考文献

• [1] Tse C, Shoemaker AR, et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008 May 1;68(9):3421-8.

  [2] Levy MA, Claxton DF, et al. Therapeutic inhibition of BCL-2 and related family members. Expert Opin Investig Drugs. 2017 Mar;26(3):293-301.

  [3] Del Gaizo Moore V, Brown JR, et al. Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest. 2007 Jan;117(1):112-21.

  [4] Chen Q, Song S, et al. ABT-263 induces apoptosis and synergizes with chemotherapy by targeting stemness pathways in esophageal cancer. Oncotarget. 2015 Sep 22;6(28):25883-96.

  [5] Ackler S, Xiao Y, et al. ABT-263 and rapamycin act cooperatively to kill lymphoma cells in vitro and in vivo. Mol Cancer Ther. 2008 Oct;7(10):3265-74.

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