Novel Cancer Therapeutics from Bench to Bedside 公开

Salgado, Eric (Fall 2018)

Permanent URL: https://etd.library.emory.edu/concern/etds/gf06g357c?locale=zh
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Abstract

Drug discovery and development from bench to bedside is a challenging endeavor, whereby 1 in about 5000 compounds which show initial promise actually succeed as a therapeutic. This multistep process consists of: target and hit discovery, hit-to-lead optimization, pharmacological and toxicological preclinical testing, and finally, human clinical trials. In order to provide a solid, broad training experience to lay the foundation for a career in drug development in industry, the work illustrated here highlights research performed at each phase of drug development. The three major targets selected for this work include: aromatase, CXCR4, and histone deacetylases.

            After appropriate target selection, drug design becomes the next major endeavor. Pre-existing results supported that an in silicoapproach would be an efficient route for the development of a novel generation of aromatase inhibitors for breast cancer. In silicostudies revealed key mechanistic similarities between existing therapies with that of our novel chemical scaffold. Furthermore, computational studies suggested a novel residue, Ser478, which may be exploited for further drug design. A second screening approach, virtual high throughput screening, was used for the development of novel anti-inflammatory CXCR4 modulators, given the flexibility of the CXCR4 binding site and from previous pharmacophore analyses. Upon identifying virtual hits, compounds were systematically screened via various preclinical assays and a comprehensive SAR study was conducted which revealed key differences in compound structure versus CXCR4 inhibitory activity. 

            Given the widely recognized roles and signaling pathways of both aromatase and CXCR4, attention was focused on the third target, histone deacetylases, and in particular, elucidating the mechanism of action of histone deacetylase inhibitors (HDACi’s). Mechanistic in vitroand in vivostudies revealed that in a cancer cell line, HDACi’s partly exert their function through the inhibition of HDAC9; in turn, suppressed HDAC9 levels restore levels of tumor suppressor miR-206, which negatively regulates invasion and angiogenesis. Finally, Phase I and ongoing Phase II clinical trials assessing the role of the HDACi belinostat in combination with standard of care in glioblastoma patients is summarized. This work provides the basis for the various methodologies required for a career in drug development in the pharmaceutical industry.

Table of Contents

Table of Contents

Abstract

 

Acknowledgements

 

Chapter 1: Scope of Drug Discovery & Development Research: An Outline..........................1

1.1  Natural products as the initial source of therapeutic relief and a driver for small molecule 

 

discovery………………………………………………………………………………………2

1.2  Brief summary of the traditional drug discovery and development process…………………....4

1.2.1     Target Identification/Validation…………………………………………..................7

1.2.2     Hit identification……………………………………………………...……………10 

1.2.2.1 High throughput-screening (HTS)………………………………………..10

1.2.2.2 in silicovirtual drug design……………………………………………….13

1.2.3     Hit-to-Lead optimization/characterization…………………..…………..................18

1.2.4     From cells to humans: clinical trials……………………………………..................22

1.2.4.1 Phase I clinical trials……………………………………………...............23

1.2.4.2 Phase II clinical trials…………………………………………………….24

1.2.4.3 Phase III clinical trials……………………………………………………24

1.2.4.4 FDA Review & Approval………………………………………...............26

1.2.4.5 Phase IV clinical trials……………………………………………………27

1.2.4.6 Concluding remarks……………………………………………...............27

Chapter 2: Fundamentals of drug design: an in silicoapproach in the development of novel aromatase inhibitors for post- menopausal, estrogen-dependent breast cancer....................28

2.1 Abstract………………………………………………………………………………………29

2.2 Background…………………………………………………………………………………..30

2.3 Materials and Methods……………………………………………………………………….33

2.4 Results………………………………………………………………………………………..36

2.5 Discussion……………………………………………………………………………………48

2.6 Supplementary Information…………………………………………………………………..52

Chapter 3: Fundamentals of drug design, Part II: vHTS in the development of novel CXCR4 modulators…………………………………………….................................................55

3.1 Abstract………………………………………………………………………………………56

3.2 Introduction…………………………………………………………………………………..57

3.3 Materials and Methods……………………………………………………………………….61

3.4 Results………………………………………………………………………………………..78

3.5 Discussion……………………………………………………………………………………93

Chapter 4: Post-drug screening preclinical mechanistic studies unraveling histone 

 

deacetylase inhibitor mode of action…………………………………………………………..97

4.1 Abstract………………………………………………………………………………………98

4.2 Introduction………………………………………………………………………………......99

4.3 Materials and Methods……………………………………………………………...............101

4.4 Results………………………………………………………………………………………105

4.5 Discussion…………………………………………………………………………………..112

Chapter 5: From cells to humans: Phase I & ongoing Phase II Clinical Trial studies assessing the effects of the HDAC inhibitor belinostat in combination with standard of care on glioblastoma patients…………….……………………………………………………………114

5.1 Abstract……………………………………………………………………………………..115

5.2 Introduction………………………………………………………………………................116

5.3 Materials and Methods……………………………………………………………...............120

5.4 Results………………………………………………………………………………………128

5.5 Discussion…………………………………………………………………………………..138

Chapter 6: General Discussion………………………………………………………………..142

6.1 General Discussion………………………………………………………………………….143

6.2 Conclusions…………………………………………………………………………………153

References……………………………………………………………………………...………154

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