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.)