Design and Synthesis of Chemical Modulators for Altered Activity of Nuclear Receptor Liver Receptor Homolog-1 and Synthesis of Spirocyclic Piperidines via Radical Hydroarylation Pubblico

Abstract

Liver Receptor Homolog-1 (LRH-1) has been implicated in human disease, particularly inflammatory bowel syndrome and pancreatic and breast cancer, due to its upregulating of genes causing lipid metabolism and stereognosis in the gut, as well as proliferation, invasion, and metastasis of tumor cells. While creating modulators to alter the activity of LRH-1 is desirable, effectively and specifically targeting this protein is extremely challenging due to the hydrophobic nature of its binding pocket. From a high through-put screen a ligand with a [3.3.0] bicyclic scaffold was identified as an agonist for LRH-1. In past iterations of agonists, we have identified an agonist with low nanomolar binding affinity. Although this is a use tool for in vitro assays, we sought to improve certain pharmacodynamic and kinetic properties to create a molecule that has improved metabolic stability and solubility properties that shows efficacy in vivo. We further sought to apply our knowledge of previously developed LRH-1 agonists to design antagonists and targeted protein degraders. Based on the structural insights from our agonist design using a [3.3.0] bicyclic scaffold, we developed a series of antagonists, where the lead compound alters the protein’s conformation, preventing recruitment of coactivators. Additionally, using compounds from our program, we constructed a bifunctional molecule capable of stimulating degradation of LRH-1 through ubiquitinoylation. After rounds of optimization, we arrived at a successful degrader capable of downregulating LRH-1 target gene expression.

Table of Contents

Chapter 1: Introduction to Nuclear Receptors. 1

1.1 Small molecule modulation on biological processes. 2

1.2 The role of nuclear receptors in the body. 3

1.3 Liver Receptor Homolog-1 as a disease target. 6

1.3.1 Liver Receptor Homolog-1 and it’s role/regulations in the body. 6

1.3.2 Small molecule manipulation of LRH-1. 7

Chapter 2: Lead optimization of Agonist Scaffold for LRH-1 for in vivo studies. 12

2.1 Introduction. 13

2.2 Results and Discussion. 14

2.2.1 Altering selectivity between LRH-1 and SF-1. 14

2.2.2 Synthesis of carboxylic acid bioisosteres series. 17

2.2.3 Addressing hydrophobicity of synthetic modulators via addition of heteroatoms. 23

2.3 Conclusion. 27

2.4 Future directions/studies. 27

2.5 Supplemental Information. 29

2.5.1 Supplemental figures. 29

2.5.2 Supporting information for section 2.2.1. 30

2.5.3 Supporting information for 2.2.2. 46

2.5.4 Supporting information for 2.2.3. 61

Chapter 3: Degradation of Liver Receptor Homolog-1 Nuclear Receptor via Proteolysis Targeting Chimeras (PROTACs). 82

3.1 Introduction. 83

3.2 Results and discussion. 85

3.3 Conclusion/Future studies. 89

3.4 Supplemental Information. 90

Chapter 4: Repurposing agonist scaffold for LRH-1 antagonism. 115

4.1 Introduction. 116

4.2 Results and discussion. 117

4.3 Conclusion. 121

4.4 Supplemental information. 122

Chapter 5: Radical Spirocyclization and photoredox hydroarylation. 167

5.1 Spirocycles in biologically active compounds. 168

5.2 The use of catalysis in order to make hard to form bonds. 169

Chapter 6: Synthesis of Spirocyclic Piperidines via Radical Hydroarylation. 172

6.1 Introduction. 173

6.2 Results and Discussion. 174

6.3 Conclusions. 177

6.4 Supporting Information. 178

References. 201

About this Dissertation

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School	Laney Graduate School
Department	Chemistry
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic
Parola chiave	Spirocyclization Chemical Biology Medicinal chemistry Spiropiperidines Organic Synthesis Photochemistry
Committee Chair / Thesis Advisor	Eric Ortlund, Emory University
Committee Members	William Wuest, Emory University Monika Raj, Emory University Nathan Jui, Loxo Oncology

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