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Ref Type Journal Article
PMID (17237275)
Authors Sha SK, Sato T, Kobayashi H, Ishigaki M, Yamamoto S, Sato H, Takada A, Nakajyo S, Mochizuki Y, Friedman JM, Cheng FC, Okura T, Kimura R, Kufe DW, Vonhoff DD, Kawabe T
Title Cell cycle phenotype-based optimization of G2-abrogating peptides yields CBP501 with a unique mechanism of action at the G2 checkpoint.
Journal Molecular cancer therapeutics
Vol 6
Issue 1
Date 2007 Jan
URL
Abstract Text Cell cycle G(2) checkpoint abrogation is an attractive strategy for sensitizing cancer cells to DNA-damaging anticancer agent without increasing adverse effects on normal cells. However, there is no single proven molecular target for this therapeutic approach. High-throughput screening for molecules inhibiting CHK1, a kinase that is essential for the G(2) checkpoint, has not yet yielded therapeutic G(2) checkpoint inhibitors, and the tumor suppressor phenotypes of ATM and CHK2 suggest they may not be ideal targets. Here, we optimized two G(2) checkpoint-abrogating peptides, TAT-S216 and TAT-S216A, based on their ability to reduce G(2) phase accumulation of DNA-damaged cells without affecting M phase accumulation of cells treated with a microtubule-disrupting compound. This approach yielded a peptide CBP501, which has a unique, focused activity against molecules that phosphorylate Ser(216) of CDC25C, including MAPKAP-K2, C-Tak1, and CHK1. CBP501 is >100-fold more potent than TAT-S216A and retains its selectivity for cancer cells. CBP501 is unusually stable, enters cells rapidly, and increases the cytotoxicity of DNA-damaging anticancer drugs against cancer cells without increasing adverse effects. These findings highlight the potency of CBP501 as a G(2)-abrogating drug candidate. This report also shows the usefulness of the cell cycle phenotype-based protocol for identifying G(2) checkpoint-abrogating compounds as well as the potential of peptide-based compounds as focused multitarget inhibitors.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
CBP501 CBP501 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
CBP501 CBP-501|CBP 501 CHK1 Inhibitor 14 CBP501 is a peptide drug that inhibits the activity of several kinases responsible for phosphorylation of CDC25C, including MAPKAP-K2, C-Tak1, and CHK1, resulting in disruption of the G2 checkpoint and potentially leading to cell-cycle arrest and increased tumor cell death (PMID: 17237275, PMID: 29088764).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown colorectal cancer not applicable Bleomycin + CBP501 Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with the combination of Blenoxane (bleomycin) and CBP501 resulted in enhanced tumor growth inhibition in cell line xenograft models of colorectal cancer, compared to either agent alone (PMID: 17237275). 17237275
Unknown unknown colorectal cancer not applicable CBP501 + Cisplatin Preclinical - Cell culture Actionable In a preclinical study, the combination of CBP501 and Platinol (cisplatin) resulted in increased cell death compared to Platinol (cisplatin) alone in a human colorectal cancer cell line in culture (PMID: 17237275). 17237275
Unknown unknown pancreatic cancer not applicable CBP501 + Cisplatin Preclinical - Cell culture Actionable In a preclinical study, the combination of CBP501 and Platinol (cisplatin) resulted in increased cell death compared to Platinol (cisplatin) alone in a human pancreatic cancer cell line in culture (PMID: 17237275). 17237275
Unknown unknown pancreatic cancer not applicable Bleomycin + CBP501 Preclinical - Cell culture Actionable In a preclinical study, the combination of Blenoxane (bleomycin) and CBP501 resulted in increased cell death compared to Blenoxane (bleomycin) alone in a human pancreatic cancer cell line in culture (PMID: 17237275). 17237275
Unknown unknown lung cancer not applicable CBP501 + Cisplatin Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with the combination of Platinol (cisplatin) and CBP501 resulted in enhanced tumor growth inhibition in cell line xenograft models of lung cancer, compared to either agent alone (PMID: 17237275). 17237275