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Discovery of Small Molecule Inhibitors of Protein-Protein Interactions

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Discovery of Small Molecule Inhibitors of Protein-Protein Interactions DISCOVERY OF SMALL MOLECULE INHIBITORS OF PROTEIN-PROTEIN INTERACTIONS by Yijun Huang Bachelor of Science, Nanjing University, 2003 Master of Science, Nanjing University, 2006 Master of Science, Texas Christian University, 2008 Submitted to the Graduate Faculty of School of Pharmacy in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2011 UNIVERSITY OF PITTSBURGH SCHOOL OF PHARMACY This dissertation was presented by Yijun Huang It was defended on November 3, 2011 and approved by Billy W. Day, Professor, Department of Pharmaceutical Sciences Barry I. Gold, Professor, Department of Pharmaceutical Sciences Judith Klein-Seetharaman, Associate Professor, Department of Structural Biology Xiang-Qun Xie, Professor, Department of Pharmaceutical Sciences Dissertation Advisor: Alexander Doemling, Professor, Department of Pharmaceutical Sciences ii Copyright © by Yijun Huang 2011 iii Discovery of Small Molecule Inhibitors of Protein-Protein Interactions Yijun Huang, Ph.D. University of Pittsburgh, 2011 Protein-protein interactions (PPIs) constitute an emerging class of targets for the next generation of therapeutic intervention. Despite their fundamental role in many biological processes and diseases such as cancer, PPIs are still largely underrepresented in drug discovery. Although small molecule PPI inhibitors are highly valuable due to a number of advantages relative to biological agents in terms of production, delivery, titratability and cost, the robust discovery of lead compounds remains a great challenge. Two structure-based drug discovery strategies are described in this work to generate small molecules to target PPIs. A receptor-based drug discovery approach can be applied when an accurate three- dimensional (3D) structure of a specific PPI complex is available. A novel, complementary and transformative approach for the rational design of small molecule inhibitors based on the crystal structure of the p53-Mdm2 complex was developed. This method is based on a tight interplay of structural biology information, the “anchor” concept, efficient chemical synthesis via multicomponent reactions (MCRs), as well as virtual and real screening processes. Applying the method we efficiently discovered several new scaffolds of inhibitors of the p53/Mdm2 interaction with lower micromolar affinity binding to Mdm2, which can serve as starting point for medicinal chemistry optimization. Advantages of our approach include high hit rates and less attrition based on the parallel discovery of multiple scaffolds, built-in optimization pathways using efficient MCRs, and fast generation of potential lead compounds. Potential anticancer drug iv candidates were identified by biochemical assays, co-crystallization, cell based assays, as well as further preclinical evaluations (solubility, metabolism, pharmacokinetics, and xenograft studies). A ligand-based drug discovery approach was explored since PPIs are critically dependent on “anchor” residues, which can serve as the pharmacophore model for small molecules. Multicomponent reactions were employed for design of novel scaffolds and DOS of drug-like compounds, since hit identification of PPI inhibitors via traditional approaches such as high throughput screening (HTS) is fundamentally limited by chemotypes present in the library collections. Novel and diverse scaffolds based on the privileged structures (1,4-benzodiazepines, 1,4-thienodiazepines) and “anchor” residues, which can be accessible from multicomponent reactions, were designed and synthesized. Compared with conventional methods, these approaches are advantageous to generate small molecules targeting PPIs in terms of efficiency, diversity, and economy. In summary, the approaches described in this dissertation constitute important contributions to the fields of medicinal chemistry and structure-based drug discovery, which combine structural insights and ligand design to expedite the discovery of novel small molecule inhibitors of PPIs. v TABLE OF CONTENTS PREFACE ................................................................................................................................. XIX 1.0 INTRODUCTION ........................................................................................................ 1 1.1 PROTEIN-PROTEIN INTERACTIONS AS DRUG TARGETS ................... 1 1.2 DISCOVERY OF SMALL MOLECULE INHIBITORS ................................ 3 1.2.1 Screening of compound libraries ................................................................. 4 1.2.2 Fragment-based drug design. ...................................................................... 6 1.2.3 Structure-based drug design. ....................................................................... 7 1.3 CURRENT RESEARCH .................................................................................... 9 2.0 DISCOVERY OF SMALL MOLECULE INHIBITORS OF P53-MDM2 INTERACTION .......................................................................................................................... 12 2.1 INTRODUCTION ............................................................................................. 12 2.2 STRUCTURE-BASED APPROACH FOR THE RATIONAL DESIGN OF P53-MDM2 INHIBITORS ................................................................................................. 17 2.3 UGI MULTICOMPONENT REACTION FOR THE DISCOVERY OF P53- MDM2 INHIBITORS ........................................................................................................ 23 2.3.1 Ugi multicomponent reaction derived p53-Mdm2 inhibitors ................. 24 2.3.2 Exhaustive fluorine scanning toward potent p53-Mdm2 inhibitors ...... 56 vi 2.4 DISCOVERY AND EVALUATION OF P53-MDM2 INHIBITORS AS POTENTIAL ANTICANCER DRUG CANDIDATES .................................................. 81 3.0 PROTEIN-PROTEIN INTERACTIONS DIRECTED LIBRARIES ................. 103 3.1 INTRODUCTION ........................................................................................... 103 3.2 DIVERSITY-ORIENTED SYNTHESIS VIA MULTICOMPONENT REACTIONS .................................................................................................................... 107 3.2.1 Synthesis of drug-like compounds via MCRs ......................................... 107 3.2.2 Discovery of novel aminothiophene scaffolds ......................................... 119 3.3 DESIGN AND SYNTHESIS OF 1,4-THIENODIAZEPINE LIBRARIES 141 3.3.1 Synthesis, virtual space and p53-Mdm2 activity .................................... 141 3.3.2 Design of anchor-directed thienodiazepine scaffold .............................. 171 3.4 DESIGN AND SYNTHESIS OF 1,4-BENZODIAZEPINES LIBRARIES 195 3.4.1 Diversity-oriented synthesis of novel benzodiazepine scaffolds............ 195 3.4.2 Design of anchor-directed benzodiazepine scaffold ............................... 211 4.0 MAJOR FINDINGS AND IMPLICATIONS ........................................................ 224 4.1 SUMMARY ...................................................................................................... 224 4.2 FUTURE DIRECTIONS................................................................................. 226 4.2.1 Directions for short-term study ............................................................... 226 4.2.2 Directions for long-term study ................................................................. 235 APPENDIX A. GENERAL METHODS ................................................................................. 236 APPENDIX B. CHIRAL SEPARATION ............................................................................... 239 APPENDIX C. AQUEOUS SOLUBILITY ............................................................................ 244 APPENDIX D. NCI-60 SCREENING .................................................................................... 252 vii APPENDIX E. VIRTUAL LIBRARIES ................................................................................. 254 APPENDIX F. LIST OF PUBLICATIONS ........................................................................... 256 BIBLIOGRAPHY ..................................................................................................................... 258 viii LIST OF TABLES Table 1. Small molecule modulators of protein-protein interactions ............................................. 2 Table 2. Screening hits of small molecule inhibitors of p53/Mdm2(Mdm4) interaction ............... 5 Table 3. Inhibitors of p53-Mdm2 interaction ............................................................................... 15 Table 4. SAR study of compounds 8 ............................................................................................ 27 Table 5. SAR study of compounds 9 ............................................................................................ 29 Table 6. Inhibition constants [μM] of compounds 17 and 18 ....................................................... 57 Table 7.Inhibition constants [μM] of pyrazole compounds .......................................................... 83 Table 8. Aqueous solubility in a phosphate buffer ....................................................................... 87 Table 9. Inhibition constants [μM] of tagged compounds ............................................................ 90 Table 10. Ugi-5-center-4-component reaction (U-5C-4CR) ...................................................... 126 Table 11. Synthesis of 1,4-thienodiazepine-2,5-diones 69a ......................................................
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