結構生物學在吡唑胺類衍生物誘導間變性淋巴激酶蛋白結構變化之分析與探討

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研究生：	涂智翔 Tu, Chih-Hsiang
論文名稱：	結構生物學在吡唑胺類衍生物誘導間變性淋巴激酶蛋白結構變化之分析與探討 Structural Biology Studies reveal the Conformational Switching of Anaplastic Lymphoma Kinase (ALK) by Pyrazolylamine Derivatives
指導教授：	伍素瑩 Wu, Su-Ying 呂平江 Lyu, Ping-Chiang
口試委員:	李惠珍 Lee, Hui-Jhen 陳俊榮 Chen, Chun-Jung 蔣維棠 Jiaang, Weir-Torn
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 生物資訊與結構生物研究所 Institute of Bioinformatics and Structural Biology
論文出版年：	2016
畢業學年度：	105
語文別：	英文
論文頁數：	260
中文關鍵詞：	蛋白結晶學、間變性淋巴瘤激酶、第一型激酶抑制劑、第二型激酶抑制劑
外文關鍵詞：	Protein crystallography, Anaplastic lymphoma kinase (ALK), Type-I kinase inhibitor, Type-II kinase inhibitor
相關次數：	點閱：1 下載：0
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研究顯示，間變性淋巴瘤激酶(Anaplastic lymphoma kinase, ALK)相關的染色體易位、基因放大以及結構中的點突變，和許多癌症的發生息息相關。因此，在使用小分子藥物做為癌症的治療上，間變性淋巴瘤激酶是一個相當有潛力的藥物靶點。截至目前為止，整理相關藥物開發的文獻，間變性淋巴瘤激酶與小分子抑制劑的結合模式大多以第一型的結合模式(Type-I kinase inhibitors)為主。雖然已有數個第一型間變性淋巴瘤激酶抑制劑已獲得美國食品藥物管理局(US FDA)認證，且在藥效(potency)的表現上相當的出色，但是多數病人在治療過程中都常伴隨著副作用的產生。因此，追求藥效更好、副作用更少的新型的間變性淋巴瘤激酶抑制劑，仍待持續不斷的研究開發。除了第一型激酶抑制劑之外，第二型的間變性淋巴瘤激酶抑制劑(Type-II kinase inhibitors)，也有望能為第一型激酶抑制劑以外的第二種選擇。但是受限於傳統的酵素活性分析的機制，目前第二型的間變性淋巴瘤激酶抑制劑的研究上相對缺乏，因此同時也限制了在分子層次下的第二型間變性淋巴瘤激酶抑制劑的開發與設計。
在此篇研究中，我們以蛋白結晶學及結構生物學的基本架構為研究方法基礎；確認前導藥物(lead) BPR-1J297與間變性淋巴瘤激酶蛋白的結合模式屬於第二型激酶抑制劑(Type-IIA kinase inhibitor)。與不同的激酶/第二型激酶抑制劑複合體作比較，在結構細部的探討中發現，BPR-1J297的結合同時會造成間變性淋巴瘤激酶中activation loop (A-loop), αC-helix, 和juxtamembrane (JM) domain構型的重大變化。這些構型變化的部位，對於在正常生理情況下間變性淋巴瘤激酶的自抑制(autoinhibition)、磷酸化(phosphorylation) 、活化(activation)以及訊息傳遞(signal pathway)的調控，扮演了相當重要的角色。除此之外，在結構與活性關係的定量化研究(structure-activity relationship, SAR)中發現，BPR-1J297化學結構上的變化不僅僅影響活性(或配體效率)，同時也造成了與間變性淋巴瘤激酶結合模式上的變化。除此之外，我們的研究方法中也包括了生物物理學上的相關研究；實驗結果證實了BPR-1J297疏水性尾端結構(urea-substituted tail moiety) 的修飾賦予了藥物結合動力學慢上慢下的特性。這樣的結果也與我們從複合體結構中得到的結果一致。在回顧過往的研究中，激酶抑制劑的結合能造成蛋白構型如此重大改變的現象並不多見，且通常缺少完整的結構上的實證。但在本篇研究中，我們清楚地證明小分子化學結構上的修飾能夠直接調控第一型與第二型的結合模式的變化，且更進一步影響了間變性淋巴瘤激酶蛋白結構的整體構型。
我們希望藉由結構生物學在間變性淋巴瘤激酶BPR-1J297以及其衍生物複合體結構的分析與探討，搭配相關物化特性的相關研究，提供一個在化學結構上的優化方向，以利於吡唑胺類衍生物在作為間變性淋巴瘤激酶抑制劑上的發展。

Studies have shown that anaplastic lymphoma kinase (ALK) chromosomal translocation, gene amplification and point mutations are associated with various human cancers. Hence, ALK has been proposed as a potential drug target in the treatment of cancers and the inhibition of irregularly activated ALK by small molecules constitutes a promising approach. Currently, most of ALK inhibitors are developed as the type-I kinase inhibitors. Although some of type-I inhibitors are FDA-approved and exhibit excellent drug potency, those are associated with some adverse effects. For this reason, continuous development of ALK inhibitors is needed. Type II kinase inhibitor is expected to be an alternative approach for the development of novel ALK inhibitors. However, only few researches have been devoted to type-II ALK inhibitor’s studies due to the limitations of the traditional enzymatic assay. Limited type-II ALK structural studies are available, which may also impede the development of the novel type-II ALK inhibitors.
In our research, protein crystallography and structural biology studies of BPR-1J297 with ALK kinase domain revealed that BPR-1J297 adopts a type-IIA binding mode. BPR-1J297, distinct from others published type-IIA inhibitors, simultaneously causes the conformational change in activation loop, αC-helix, and juxtamembrane domain of ALK, which are all important domains for ALK autoinhibition, phosphorylation, activation, and downstream signal pathway regulation. The structure-activity relationship (SAR) of BPR-1J297 reveals that minor modifications to the chemical structure of BPR-1J297 led to significant differences in the ALK potency (or ligand efficiency) as well as alters the binding mode between type-I and type-II in ALK. In addition, biophysics studies were performed and that hydrophobic urea-substituted tail moiety endowed BPR-1J297 with slow association rate and dissociation rate, in consistent with the results in structure biology studies. To our knowledge, this is the first research comprehensively demonstrated that chemical modification in a small molecule structure can directly regulate the switch between the type I and type II binding modes, and induce dramatic conformational changes in protein structures.
Structural biology studies of ALK in complex with BPR-1J297 and its analogues together with the physicochemical properties studies provide the insights on the future chemical structural optimization of pyrazolylamine series as potential ALK inhibitors in the treatment of cancer reagents.

Table of Contents    3
List of Figures    7
List of Tables    11
List of Appendix    12
Abbreviation    13
Abstract    15
中文摘要    17
誌謝    19

Chapter 1 Introduction    20
1    Characteristic of Kinase in Human Cancer    20
1.1    Classification of Protein Kinases    20
1.2    Molecular Mechanism of Tyrosine Kinases    22
1.3    Tyrosine Kinases in Human Cancer    25
1.4    Tyrosine Kinase Architecture    27
2    Small Molecular Kinase Inhibitors    30
2.1    FDA-approved Small Kinase Inhibitors    30
2.2    Type-I Kinase Inhibitors    33
2.3    Type-II Kinase Inhibitors    37
2.3.1    Background    37
2.3.2    Type-II Kinase Inhibitor Pharmacophores    41
2.4    Type-III, Type-IV, and Type-V Kinase Inhibitors    44
2.5    Type-VI Kinase Inhibitors: Irreversible Kinase Inhibitors    45
2.6    The Common Lipophilicity Indexes for Drug Development    47
3    Anaplastic Lymphoma Kinase (ALK)    51
3.1    Background    51
3.2    The Role of ALK in Human Cancer    52
3.3    FDA-approved ALK Inhibitors    53
3.4    Clinical Development of ALK Inhibitors    58
3.5    Overview of ALK Kinase Domain Structure    59
3.6    ALK Structure Adopts an Inactive Conformation    62
4    Research Niche and Purpose    67

Chapter 2. Material and Method    69
1    Materials    70
2    Baculovirus Transfer Vector Construction    70
2.1    pBacPAK-8 Transfer Vector Construction    70
2.2    Site-Direct Mutagenesis    74
3    Insect Cell Culture    76
3.1    Cell Culture    76
3.2    Baculovirus Transfer Vector Transfection    76
3.3    Selection of a Single Baculovirus Colony    79
3.4    Western Blotting    79
3.5    Baculovirus Amplification    80
3.6    Virus Titer Estimation    81
4    Protein Expression and Purification    82
5    ALK Crystallization    84
5.1    Protein Crystallization    84
5.2    Micro-seeding    84
5.3    ALK Crystal Soaking    85
6    Data Collection and Structure Refinement    87
7    ALK Kinase Inhibition Assay    88
8    Surface Plasmon Resonance (SPR)    90
8.1    Biacore System    90
8.2    Sensor Chip Immobilization    90
8.3    Binding Kinetic and Steady-state Analysis    93
9    Molecular Docking    95
10    Circular Dichroism (CD) Spectroscopy    97

Chapter 3. Research Results of ALK Protein Expression, Purification, and Crystallization    99
1    pBakPAK-8 Transfer Vector Construction    100
2    pBakPAK-8-ALK Transfection    102
2.1    ALK Protein Expression    106
2.2    ALK Identification and Homogeneity Analysis    108
2.1    ALK Protein Purification    113
3    ALK Protein Crystallization    117

Chapter 4. Research Results of the Crystal Structure of ALK/BPR-1J297 and its Analogous    122
1    Crystal Structure apo ALK    123
2    Structure-Activity relationships (SAR) of BPR-1J297 and its Analogous        129
3    Crystal Structure of ALK/BPR-1J297 and its Analogous Structures    134
4    Binding of BPR-1J297 induced a Dramatic Conformation Change in ALK    145
4.1    Rearrangement of Activation Loop (A-loop) and αC-helix    145
4.2    Conformational Change of Juxtamembrane (JM) Domain    155
4.3    Transposition of Phosphotyrosine Residues in the Juxtamembrane (JM) Domain    157
5    The Effect of the Urea-substituted Tail Moiety of BPR-1J297 on ALK Binding    160
6    Binding Kinetics of BPR-1J297, BPR-1J452, and Crizotinib by Surface Plasmon Resonance (SPR) Method    165
7    Comparisons of ALK/BPR-1J297 with others ALK Kinase Inhibitor Complex Structures    172
8    Structure-Guided Leads Optimization of BPR-1J297    179

Chapter 5. Research Results of Crystal Structure of ALK/BPR-1J416 and its Derivatives    186
1    Structure-Activity relationship (SAR) of BPR-1J416 and its Analogous            187
2    Kinase Profiling against BPR-1J416 and BRR-1J297    191
3    Crystal Structure of ALK/BPR-1J416 and its Analogous Structures    192
4    Binding of BPR-1J416 induced the Local Conformation change in ALK        200
4.1    Refolding of Phosphate-Binding Loop (P-loop)    200
4.2    Rearrangement of Activation Loop (A-loop)    203
5    The Effect of the Hydrophobic Tail Moiety of BPR-1J416 on ALK Binding    206
6    Comparisons of ALK/BPR-1J416 Structure with ALK/BPR-1J297 Structure    213

Chapter 6. Discussion and Conclusion    218
Appendix    226
Reference    240
Publication    259


                                

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