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, Hadas Reuveni*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

A platform for specifically modulating kinase-dependent signaling using peptides derived from the catalytic domain of the kinase is presented. This technology, termed KinAce™, 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.

Original languageAmerican English
Pages (from-to)1242-1255
Number of pages14
JournalJournal of Biological Chemistry
Volume279
Issue number2
DOIs
StatePublished - 9 Jan 2004
Externally publishedYes

Fingerprint

Dive into the research topics of 'Sequence-based Design of Kinase Inhibitors Applicable for Therapeutics and Target Identification'. Together they form a unique fingerprint.

Cite this