Modulation of oncogenic kinase activity using an allosteric regulatory domain-binding protein binder알로스테릭 조절 도메인 특이적인 결합 단백질을 이용한 종양 유발 인산화효소의 활성 조절에 관한 연구

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Protein kinases are involved in numerous functions such as cell growth, migration, and metabolism. However, oncogenic kinases cause various cancers or diseases due to an expression of oncogene. The development of therapeutic agents for Bruton’s tyrosine kinase (Btk), which is the cause of B-cell lymphoma, was mainly focused on small-molecule inhibitors targeting the ATP-binding site. However, these inhibitors interact non-specifically with numerous proteins with homologous amino acids within ATP-binding sites, resulting in serious side effects. In addition, there is a great disadvantage that the drug efficacy is decreased by generating a drug resistance mutation. In this thesis, we investigated the function of allosteric regulatory domain of Btk and developed a specific repebody to demonstrate the inhibitory effect of Btk activity. In Chapter 1, we investigated the development of repebody specific for allosteric regulatory domain of Btk. First, we constructed a docking model using a computationally-driven docking algorithm to identify the positive function of the allosteric regulatory domain, and identified key residues involved in regulating Btk activity. Based on the result, we have successfully developed a repebody with high affinity and specificity in the allosteric regulatory domain by phage display. The developed repebody effectively inhibited the Btk activity compared with ibrutinib, which is a small-molecule inhibitor for Btk, and proved to be effective in drug resistance mutations. In addition, repebody blocked the activity of downstream kinases of Btk in B cell lymphoma and inhibited cell growth. This demonstrates the possibility of a notable protein drug for the treatment of B cell lymphoma such as chronic lymphocytic leukemia (CLL). In Chapter 2, we have successfully identified the inhibition mechanism of repebody for Btk, which was developed using computationally-driven binding interface prediction approach. In order to apply a new algorithm for predicting the binding interface of two proteins, we successfully demonstrated the prediction of the binding interface of repebody using IgG and IgG-specific repebody (RbF4) as model proteins. Based on this, we predicted the binding interface of the repebody specific for the allosteric regulatory domain of Btk and explained the inhibition mechanism of Btk activity. In this thesis, we study that the allosteric regulatory domain has a possibility of a new drug target that can effectively modulate the activity of oncogenic kinases and develop a protein binder specific for the allosteric regulatory domain to prove the possibility as a candidate for a new therapeutic agent applicable to various oncogenic kinases.
Advisors
Kim, Hak-Sungresearcher김학성researcher
Description
한국과학기술원 :생명과학과,
Publisher
한국과학기술원
Issue Date
2019
Identifier
325007
Language
eng
Description

학위논문(박사) - 한국과학기술원 : 생명과학과, 2019.2,[viii, 76 p. :]

Keywords

B cell lymphoma▼aoncogenic kinase▼aBruton's tyrosine kinase▼aallosteric regulatory domain▼arepebody; B세포림프종▼a종양 유발 인산화효소▼a브루톤 티로신 키나아제▼a알로스테릭 조절 도메인▼a리피바디

URI
http://hdl.handle.net/10203/264781
Link
http://library.kaist.ac.kr/search/detail/view.do?bibCtrlNo=842102&flag=dissertation
Appears in Collection
BS-Theses_Ph.D.(박사논문)
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