生物活性

• 靶点	p97 IC50:11nM

• 描述CB-5083 is a potent, ATP-competitive, D2-selective p97 inhibitor with IC50 value of 11nM against p97 ATPase activity. CB-5083 exhibited cell killing effect on >300 tumor cell lines tested with IC50 values ranging in 115-2000 nM, and poly-Ub accumulation in 12 tumor cell lines tested with IC50 values ranging in 150-800 nM. Oral administration of CB-5083 at dose of 75 mg/kg, qd, for 14 days suppressed tumor growth of Nu/Nu nude female mice bearing established human tumor xenografts derived from HCT 116 colon. Treatment with CB-5083 at a dose of 100 mg/kg on a qd4on/3off weekly schedule suppressed tumor growth in AMO-1 multiple myeloma model, which showed similar efficiency with bortezomib. However, bortezomib failed to suppress tumor growth in A549 lung carcinoma model, while CB-5083 showed potency to the same model. This suggested that CB-5083 could potentially be effective against both hematologic and solid tumors^[1].
• 作用机制CB-5083 is an ATP-competitive p97 inhibitor through specifically interacting with D2 site which is primarily responsible for the ATPase activity of p97.^[1]

• 动物研究
  剂量	Nude Mice: 25 mg/kg - 100 mg/kg[2] (p.o.), 150 mg/kg[1] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Nude mice[1] Dose 3.0 mg/kg (i.v.) 25 mg/kg (p.o.) Administration i.v. p.o. F 41% (p.o.) AUCinf 8.42 h·μM (i.v.) 28.94 h·μM (p.o.) T1/2 2.83 h (i.v.) 2.56 h (p.o.) Tmax 0.50 h (p.o.) AUClast 8.38 h·μM (i.v.) 28.89 h·μM (p.o.) Vss 418.0 ml/kg (i.v.) MRT 1.17 h (i.v.) 3.05 h (p.o.) C0 25.7 μM (i.v.) Cmax 7.95 μM (p.o.) CL 5.9 ml/min/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
  NCT02243917	Advanced Solid Tumors	Phase 1	Terminated(MTD determined)	-	United States, Arizona ... more >> HonorHealth Research Institute Scottsdale, Arizona, United States, 85258 United States, California Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute Los Angeles, California, United States, 90048 University of California San Francisco San Francisco, California, United States, 94115 United States, Colorado University of Colorado Aurora, Colorado, United States, 80045 United States, Georgia Winship Cancer Institute of Emory University Atlanta, Georgia, United States, 30322 United States, Pennsylvania University of Pennsylvania, Abramson Cancer Center Philadelphia, Pennsylvania, United States, 19104 Collapse <<
  NCT02223598	Lymphoid Hematological Maligna... more >>ncies Relapsed and Refractory Multiple Myeloma Collapse <<	Phase 1	Terminated(MTD determined)	-	United States, California ... more >> City of Hope National Medical Center Duarte, California, United States, 91010 University of California, San Francisco San Francisco, California, United States, 94143 United States, Georgia Emory University Atlanta, Georgia, United States, 30322 United States, Maryland RCCA MD Bethesda, Maryland, United States, 20817 United States, Missouri Washington University Saint Louis, Missouri, United States, 63110 United States, New Jersey Hackensack University Medical Center Hackensack, New Jersey, United States, 07601 Canada, Ontario Princess Margaret Cancer Centre Toronto, Ontario, Canada, M5G 2M9 Canada, Quebec Cedars Cancer Centre, McGill University Health Centre Montreal, Quebec, Canada, H4A 3J1 Collapse <<

• 参考文献

• [1] Zhou HJ, Wang J, et al. Discovery of a First-in-Class, Potent, Selective, and Orally Bioavailable Inhibitor of the p97 AAA ATPase (CB-5083). J Med Chem. 2015 Dec 24;58(24):9480-97.

  [2] Anderson DJ, Le Moigne R, et al. Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis. Cancer Cell. 2015 Nov 9;28(5):653-665.