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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.

SUBMITTER: Shen Q

PROVIDER: S-EPMC6072116 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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

Shen Qingliang Q Bhatt Veer S VS Krieger Inna I Sacchettini James C JC Cho Jae-Hyun JH

MedChemComm 20180201 3

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 i ...[more]

PMID: 30108942

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Project description:The human Abl kinases comprise a family of proteins that are known to be key stimulus drivers in the signaling pathways modulating cell growth, cell survival, cell adhesion, and apoptosis. Recent collative studies have indicated the role of activation of Abl and Abl-related genes in solid tumors; further terming the Abl kinases as molecular switches which promote proliferation, tumorigenesis, and metastasis. The up-regulated Abl-kinase expression in colorectal cancer (CRC) and the role of Abl tyrosine kinase activity in the Matrigel invasion of CRC cells have cemented its significance in CRC advancement. Therefore, the requisite of identifying small molecules which serve as Abl selective inhibitors and designing anti-Abl therapies, particularly for CRC tumors, has driven this study. Curcumin has been touted as an effective inhibitor of cancer cells; however, it is limited by its physicochemical inadequacies. Hence, we have studied the behavior of heterocyclic derivatives of curcumin via computational tools such as pharmacophore-based virtual screening, molecular docking, free-energy binding, and ADME profiling. The most actively docked molecule, 3,5-bis(4-hydroxy-3-methylstyryl)-1H-pyrazole-1-carboxamide, was comparatively evaluated against Curcumin via molecular dynamics simulation using Desmond, Schrödinger. The study exhibited the improved stability of the derivative as compared to Curcumin in the tested protein pocket and displayed the interaction bonds with the contacted key amino acids. To further establish the claim, the derivatives were synthesized via the mechanism of cyclization of Curcumin and screened in vitro using SRB assay against human CRC cell line, HCT 116. The active derivative indicated an IC50 value of 5.85 µM, which was sevenfold lower as compared to Curcumin's IC50 of 35.40 µM. Hence, the results base the potential role of the curcumin derivative in modulating Abl-kinase activity and in turn may have potential therapeutic value as a lead for CRC therapy.Supplementary informationThe online version contains supplementary material available at 10.1007/s13205-021-03051-9.

Dataset Information

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

Publications

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

Similar Datasets

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