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Discovery of Small Molecule and Peptide-Based Ligands for the Methyl-Lysine Binding Proteins 53Bp1 and Phf1/Phf19

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Discovery of Small Molecule and Peptide-Based Ligands for the Methyl-Lysine Binding Proteins 53Bp1 and Phf1/Phf19 DISCOVERY OF SMALL MOLECULE AND PEPTIDE-BASED LIGANDS FOR THE METHYL-LYSINE BINDING PROTEINS 53BP1 AND PHF1/PHF19 Michael Thomas Perfetti A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Division of Chemical Biology and Medicinal Chemistry in the Doctoral Program of the UNC Eshelman School of Pharmacy. Chapel Hill 2015 Approved by: Stephen Frye David Lawrence Albert Bowers Brian Strahl Greg Gang Wang Andrew Lee © 2015 Michael Thomas Perfetti ALL RIGHTS RESERVED ii ABSTRACT Michael Thomas Perfetti: Discovery of Small Molecule and Peptide-based Ligands for the Methyl-Lysine Binding Proteins 53BP1 and PHF1/PHF19 (Under the direction of Stephen V. Frye) Improving the understanding of the role of chromatin regulators in the initiation, development, and suppression of cancer and other devastating diseases is critical, as they are integral players in the regulation of DNA integrity and gene expression. Developing chemical tools for histone binding proteins that possess cellular activity will allow for further elucidation of the specific function of this class of histone regulating proteins. This research specifically targeted two different classes of Tudor domain containing histone binding proteins that are directly involved in the DNA damage response and modulation of gene transcription activities. The first methyl-lysine binding protein targeted was 53BP1, which is a DNA damage response protein. 53BP1 uses a tandem tudor domain (TTD) to recognize histone H4 dimethylated on lysine 20 (H4K20me2), a post-translational modification (PTM) induced by double-strand DNA breaks. Through a cross- screening approach, two different small molecule ligands were identified for the 53BP1 TTD. Medicinal chemistry and structure-based design techniques were used, in addition to the development of a fragment-based screen, toward the goal of optimizing the potency and selectivity of the identified small molecule ligands. The later small molecule ligand, 61 (UNC2170), was further optimized as a micromolar inhibitor of 53BP1, which demonstrated a 17-fold selectivity iii for 53BP1 TTD as compared to other screened methyl-lysine (Kme) binding proteins. Structural studies revealed that the N-tert-butyl amine of 61 (UNC2170) anchors the compound in the Kme binding pocket of 53BP1 TTD, making it competitive with endogenous Kme substrates. X-ray crystallography demonstrated that 61 (UNC2170) bound at the interface between two tudor domains of a 53BP1 TTD dimer. Importantly, this compound functions as a 53BP1 antagonist in cellular lysates and shows cellular activity by suppressing class switch recombination, a process that requires a functional 53BP1 tudor domain. These results demonstrate that 61 (UNC2170) is a functionally active, fragment-like ligand for 53BP1 and the first selective small molecule ligand discovered for 53BP1 TTD. Additional research efforts were focused toward development of peptide-based ligands for the histone binding proteins PHF1 and PHF19. These proteins play an active role in the modulation of PRC2 activity that in turn controls various gene expression and repression outcomes. Structure- based design techniques were used to design peptide-based inhibitors for PHF1 and PHF19. Research efforts were focused on conducting an initial Structure Activity Relationship (SAR) study to develop a short, low molecular weight peptide via truncation of the endogenous histone 3 peptide. Structure based design techniques were used to develop a shorter 6- or 7-mer peptide that possessed various amino acid substitutions that specifically bound within the Tudor domain of PHF1 and PHF19 with emphasis on determining a quaternary amine mimic for the tri-methyl lysine 36 residue. These efforts proved fruitful and a 7-mer peptide (148) was developed that was equipotent to the endogenous histone peptide. iv Research efforts on both of these targeted proteins demonstrates that structure based design and medicinal chemistry techniques can successfully facilitate the development of small molecule and peptide based ligands for histone binding proteins. v To my family. vi ACKNOWLEDGEMENTS I would like to extend my sincerest gratitude to my family and friends for their continued support, encouragement, and continued love throughout my graduate training. This would have never been possible without their continued support. Most importantly, I would like to thank my Mom, Dad, and Brother (Patty, Tom and David), for always being there and supporting and encouraging me through this experience to achieve my goals. I could never have completed such a journey without you. Thank you! I would like to thank my dissertation committee for their guidance and continued commitment to my scientific development. To my advisor, Dr. Stephen Frye: You have truly been an amazing mentor and advisor throughout my graduate training and I cannot thank you enough for all of the support, advice, and friendship that you have willingly provided me with over the years. Thank you so very much for helping me to achieve my goals. I wish to thank my committee chair, Dr. David Lawrence, who has always provided insightful advice and constructive humor in regards to on my scientific and professional development and for that, I am very grateful. I thank wish to thank the rest of my committee members, Dr. Brian Strahl, Dr. Greg Wang, and Dr. Albert Bowers, for all of their support and constructive suggestions and conversations during committee meetings, recruitment weekends, and our collaboration on the research projects described in this dissertation. I wish to thank all of the current and past members of the Frye laboratory and the Center for Integrative Chemical Biology and Drug Discovery. Your support and friendship have made the challenges and obstacles encountered in graduate school easier to endure. I wish to sincerely thank Dr. Lindsey Ingerman, Dr. Brandi Baughman, Dr. Bradley Dickson, Dr. Scott Rothbart, Dr. Jacqueline L. Norris, Dr. vii Samantha Pattenden, Mr. Chatura Jayakody, Dr. Nancy Cheng, Dr. Dmitri Kireev, Mr. William Janzen and other members of the CICBDD, Strahl, Bedford, McBride, Mer and SGC Toronto research labs for their contributions to this project. Lindsey, this would not have been possible without your excellent guidance and support, thank you! I extend my sincerest gratitude to Jake Stuckey, Kim Barnash, and Junghyun Lee for working together as a group of graduate students in the Frye Lab and helping each other grow. Barbara Dearry, Thank you so much for keeping me on schedule and motivated in the CICBDD. I wish to say thank you to my close friends Colin O’Banion, Matt Geden, Stephen Capuzzi, Dr. Deepak Jha, Dr. Aaron Nile, Dr. Cindy Gode, Dr. Lance Thurlow, Szymon Karwowski, Dr. Eric Montijo, and Ethan Suttles for their continuous love and support throughout the past few years. You’ve made this journey a blast and I could not thank you more for being there for me and for all the friendship, encouragement, advice, support during my graduate training. The University of North Carolina at Chapel Hill has been and will always be my home and I could ask more of this amazing institution over the past five years of my graduate training. Thank you so very much! viii PREFACE This Ph.D. thesis was initiated and completed in the Division of Chemical Biology and Medicinal Chemistry in the Doctoral Program of the UNC Eshelman School of Pharmacy at UNC-Chapel Hill. Work described in Chapter 2 including several figures and adapted text has been reproduced in part from “Identification of a Fragment-like Small Molecule Ligand for the Methyl-lysine Binding Protein, 53BP1”, (in press) with permission from ACS Chemical Biology. Unpublished work copyright 2015 American Chemical Society." ix TABLE OF CONTENTS LIST OF TABLES…………………………………………………………………………………….xviii LIST OF FIGURES…………………………………………………………………………………….xix LIST OF ABBREVIATIONS AND SYMBOLS……………………………………………………xxii CHAPTER 1: DEVELOPMENT OF METHYL-LYSINE INHIBITORS…………………………..1 Background……………………………………………………………………………………….1 Post-Translational Modifications (PTMs) and their role in chromatin regulation………………………………………………………………….3 Classes of methyl-lysine binding proteins……………………………………………………...5 Interpretation of specific PTMs by methyl-lysine binding proteins…………………5 Tudor binding domain…………………………………………………………………...6 Hypothesized outcomes of domain inhibition…………………………………………8 Current state of ligand development for methyl-lysine binding proteins……………………9 Challenges toward development of inhibitory ligands for methyl-lysine binding proteins…………………………………………………………9 Current examples of inhibitory ligands………………………………………………10 Use of Hit discovery techniques to discover inhibitory ligands…………………………….13 x Methyl-lysine binding protein biological screening methods ……………………..13 Structure-based drug design……………………………………………………….….13 Purpose of this work……………………………………………………………………………14 CHAPTER 2: DESIGN, SYNTHESIS, AND CHARACTERIZATION OF SMALL MOLECULE LIGANDS FOR THE CHROMATIN METHYL-LYSINE BINDER, 53BP1………………………………………………………………...15 Discovery and biological function of 53BP1…………………………………………………15 DNA Repair Pathways, BRCA Mutations, and Cancer……………………………………..17 Use of medicinal chemistry techniques to discover inhibitory ligands for 53BP1…………………………………………………………..19 Purpose of this work……………………………………………………………………………20 Benzimidazole-based small molecule ligand of 53BP1, UNC1554…………………………………22 Results and discussion………………………………………………………………………….22
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