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Research Articles: Therapeutics, Targets, and Development

Cell cycle phenotype-based optimization of G₂-abrogating peptides yields CBP501 with a unique mechanism of action at the G₂ checkpoint

¹ CanBas Co. Ltd., Numazu, Japan; ² Fazix Co., New York, New York; ³ MDS Pharma Services, Taipei, Taiwan; ⁴ School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan; ⁵ Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; and ⁶ Arizona Cancer Center, University of Arizona, Tucson, Arizona

Requests for reprints: Takumi Kawabe, CanBas Co. Ltd., Makiya Building 5F, 9 Tooriyoko-cho, Numazu 410-0891, Japan. Phone: 81-55-954-3666; Fax: 81-55-954-3668. E-mail: takumi{at}canbas.co.jp

Abstract

Cell cycle G₂ 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 G₂ checkpoint, has not yet yielded therapeutic G₂ checkpoint inhibitors, and the tumor suppressor phenotypes of ATM and CHK2 suggest they may not be ideal targets. Here, we optimized two G₂ checkpoint-abrogating peptides, TAT-S216 and TAT-S216A, based on their ability to reduce G₂ 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 Ser²¹⁶ 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 G₂-abrogating drug candidate. This report also shows the usefulness of the cell cycle phenotype-based protocol for identifying G₂ checkpoint-abrogating compounds as well as the potential of peptide-based compounds as focused multitarget inhibitors. [Mol Cancer Ther 2007;6(1):147–53]

Grant support: Japanese Ministry of Economy, Trade, and Industry; Shizuoka Organization for Creation of Industries; Toyota Motor Co. Ltd.; and Olympus Co. Ltd.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 6/26/06; revised 11/ 6/06; accepted 11/16/06.