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]
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