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Structure-guided design of a potent peptide inhibitor targeting the interaction between CRK and ABL kinase

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Abstract

CT-10 regulator of kinase (CRK) proteins play important roles in human cancer metastasis and invasion. Moreover, CRK proteins are the major phosphorylation substrates of ABL kinase and its oncogenic mutant BCR-ABL kinase. The interaction between CRK and BCR-ABL plays important roles in chronic myeloid leukemia. Hence, inhibiting the interaction of CRK with BCR-ABL is an attractive way to attenuate cancer metastasis. Herein, we report the development of a peptide inhibitor, PRM-3, targeting the interaction between CRK-II and ABL kinase. PRM-3 binds to the N-terminal SH3 (nSH3) domain in CRK-II with a 10 nM affinity and prevents the interaction between CRK-II and ABL kinase. An in vitro biochemical assay demonstrated that PRM-3 inhibits the ABL-dependent phosphorylation of CRK-II more effectively than imatinib. Remarkably, PRM-3 also inhibited the CRK phosphorylation by T315I-ABL kinase, which is resistant to all first- and second-generation tyrosine kinase inhibitors. Our study provides a promising alternative approach to overcome the drug resistance of ABL kinase.

Graphical abstract: Structure-guided design of a potent peptide inhibitor targeting the interaction between CRK and ABL kinase

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Publication details

The article was received on 07 Dec 2017, accepted on 26 Jan 2018 and first published on 01 Feb 2018


Article type: Research Article
DOI: 10.1039/C7MD00619E
Citation: Med. Chem. Commun., 2018, Advance Article
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    Structure-guided design of a potent peptide inhibitor targeting the interaction between CRK and ABL kinase

    Q. Shen, V. S. Bhatt, I. Krieger, J. C. Sacchettini and J. Cho, Med. Chem. Commun., 2018, Advance Article , DOI: 10.1039/C7MD00619E

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