A regulatory SH2 domain-targeting protein binder effectively inhibits the activity of Bruton's tyrosine kinase and its drug-resistant variants.
Human Bruton's tyrosine kinase (hBtk) plays a key role in growth and metabolism of B cells, but its dysfunctions cause various B-cell malignancies. Inhibitors targeting the ATP-binding pocket of hBtk have been developed, but they have several drawbacks such as adverse side effects and occurrence of drug-resistant mutations. Here, we present a protein binder which specifically binds to an allosteric regulatory SH2 domain of hBtk. The protein binder effectively inhibited the hBtk activity, indicating a critical role of the SH2 domain in allosteric regulation of the hBtk activity. Cytosolic delivery of the protein binder led to a significant inhibition on the BCR-mediated signaling and viability of B lymphoma cells. The utility of our approach was demonstrated by effective inhibition of drug-resistant hBtk variants by the protein binder. Based on the computationally predicted binding mode, the protein binder is likely to inhibit the hBtk activity by disrupting the interaction between the SH2 domain and kinase domain. The present approach can be used for developing therapeutic agents with improved efficacy for B-cell lymphoma.
['Jeong|Sukyo|S|', 'Sohn|Yoo-Kyoung|YK|', 'Choi|Yoonjoo|Y|', 'Park|Jinho|J|', 'Kim|Hak-Sung|HS|']
D000077329:Agammaglobulinaemia Tyrosine Kinase D000970:Antineoplastic Agents D045744:Cell Line, Tumor D003600:Cytosol D019008:Drug Resistance, Neoplasm D006801:Humans D016393:Lymphoma, B-Cell D008958:Models, Molecular D009154:Mutation D011485:Protein Binding D047428:Protein Kinase Inhibitors D018909:src Homology Domains
SH2 Protein binder B-cell lymphoma Allosteric regulatory domain Bruton’s tyrosine kinase Repebody