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

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.

• Authors: Qingliang Shen, Veer S Bhatt, Inna Krieger, James C Sacchettini, Jae-Hyun Cho
• Journal: MedChemComm (Medchemcomm) Vol. 9 Issue 3 Pg. 519-524 (Mar 01 2018) ISSN: 2040-2503 [Print] England
• PMID: 30108942 (Publication Type: Journal Article)