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J. Biol. Chem., Vol. 279, Issue 2, 1242-1255, January 9, 2004

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Sequence-based Design of Kinase Inhibitors Applicable for Therapeutics and Target Identification^*

Masha Y. Niv, Hila Rubin, Jacob Cohen, Lilia Tsirulnikov, Tamar Licht, Adi Peretzman-Shemer, Einat Cna'an, Alexander Tartakovsky, Ilan Stein, Shira Albeck, Irina Weinstein, Mirela Goldenberg-Furmanov, Dror Tobi, Einat Cohen¶, Morris Laster, Shmuel A. Ben-Sasson¶, and Hadas Reuveni||

From the Keryx Biopharmaceuticals, 15 Yad-Haruzim St., Jerusalem 93420, Israel and the ^¶Department of Experimental Medicine and Cancer Research, The Hebrew University-Hadassah Medical School, P. O. Box 12272 Jerusalem, Israel

A platform for specifically modulating kinase-dependent signaling using peptides derived from the catalytic domain of the kinase is presented. This technology, termed KinAce^TM, utilizes the canonical structure of protein kinases. The targeted regions (subdomain V and subdomains IX and X) are analyzed and their sequence, three-dimensional structure, and involvement in protein-protein interaction are highlighted. Short myristoylated peptides were derived from the target regions of the tyrosine kinases c-Kit and Lyn and the serine/threonine kinases 3-phosphoinositide-dependent kinase-1 (PDK1) and Akt/protein kinase B (PKB). For each kinase an active designer peptide is shown to selectively inhibit the signaling of the kinase from which it is derived, and to inhibit cancer cell proliferation in the micromolar range. This technology emerges as an applicable tool for deriving sequence-based selective inhibitors for a broad range of protein kinases as hits that may be further developed into drugs. Moreover, it enables identification of novel kinase targets for selected therapeutic indications as demonstrated in the KinScreen application.

Received for publication, June 25, 2003 , and in revised form, October 6, 2003.

^* 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.

The on-line version of this article (available at http://www.jbc.org) contains Appendix A, Appendix B, and Refs. 94-100.

Both authors contributed equally to this work.

^|| To whom correspondence should be addressed. Tel.: 972-2-6732910; E-mail: hadas{at}keryx.com.

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