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1 Expert Intelligence for Better Decisions Epigenetics: Emerging Targets, Available Technologies, Expert Interviews, and an Epigenetic Community Perspective

2 Using This Document Insight Pharma Reports are interactive electronic documents which offer many of the features of Web sites, including navigation, search, bookmarks, download options, and additional layered content. A navigation bar containing links to the Table of, a feature, Previous/Next page arrows, and a Return button is anchored at the bottom of each page. Hyperlinks throughout the document are designated by blue, underlined text. Hyperlinks on the Index page are also rendered as blue text, and will navigate you to a company s Web site. Table of listings are hyperlinked and will navigate you directly to that specific content, Table or Figure. Reports are also available in printed format References can be accessed by clicking directly on the Reference number. There is also a References page at the end of the document. To order copies of this report, customized for your organization, contact: Rose LaRaia P E rlaraia@healthtech.com Next Page Return This button will return you to a previously visited, non-sequential page Access the Table of the Report Insight Pharma Reports Web site Visit our site to research additional Report titles Previous Page i

3 Insight Pharma Reports Single User License This License permits only the Licensee with individual access to the report. This license consists of an electronic report PDF and allows for perpetual access. You may not sell, rent or lease any part of the report to the general public. Insight Pharma Reports Multi-User License This License permits up to 5 Licensees with access to the report. This license consists of an electronic report PDF and allows for perpetual access. You may not sell, rent or lease any part of the report to the general public. Insight Pharma Reports Single Site License This License permits the Licensee to share or distribute the contents of the report with all company or organization employees at the same site or physical location. This License also permits the Licensee to share or distribute the contents of the report with all employees of a company or organization subsidiary at the same site or physical location. This license consists of an electronic report PDF and allows for perpetual access. You may not sell, rent or lease any part of the report to the general public. Insight Pharma Reports Multi-Site License This License permits the Licensee to share or distribute the contents of the report with all company or organization employees worldwide. This License also permits the Licensee to share or distribute the contents of the report with all employees of a company or organization subsidiary. This license consists of an electronic report PDF and allows for perpetual access. You may not sell, rent or lease any part of the report to the general public. ii

4 Epigenetics: Emerging Targets, Available Technologies, Expert Interviews, and an Epigenetic Community Perspective Published in Ocotber 2013 by Cambridge Healthtech Institute iii

5 Insight Pharma Reports is a division of Cambridge Healthtech Institute, a world leader in life science information and analysis through conferences, research reports, and targeted publications. Insight Pharma Reports focus on pharmaceutical R&D the technologies, the companies, the markets, and the strategic business impacts. They regularly feature interviews with key opinion leaders; surveys of the activities, views, and plans of individuals in industry and nonprofit research; and substantive assessments of technologies and markets. Managers at the top 50 pharma companies, the top 100 biopharma companies, and the top 50 vendors of tools and services rely on Insight Pharma Reports as a trusted source of balanced and timely information. Managing Director: Science Writer: Design Director: Production Director: Customer Service: Corporate Subscriptions: Lisa Scimemi , lscimemi@healthtech.com Chelsea Macary , cmacary@healthtech.com Thomas Norton , tnorton@healthtech.com Ann Marie Handy , ahandy@healthtech.com Rose LaRaia , rlaraia@healthtech.com David Cunningham , cunningham@healthtech.com iv

6 Epigenetics: Emerging Targets, Available Technologies, Expert Interviews, and an Epigenetic Community Perspective For more information about published Insight Pharma Reports, visit or call Rose LaRaia at A Cambridge Healthtech Institute publication 2012 by Cambridge Healthtech Institute (CHI). This report cannot be duplicated without prior written permission from CHI. Every effort is made to ensure the accuracy of the information presented in Insight Pharma Reports. Much of this information comes from public sources or directly from company representatives. We do not assume any liability for the accuracy or completeness of this information or for the opinions presented. Cambridge Healthtech Institute, 250 First Avenue, Suite 300, Needham, MA Phone: n Fax: n v

7 Executive Summary Executive Summary This report covers several overview aspects of epigenetics including current targets under investigation and rising technologies of participating companies. These companies have kindly disclosed several strategies, methods, and techniques that they use for either target identification or technology development. Part I describes background information of the topics discussed in this report, particularly several targets of interest including histone methyltransferases, histone demethylases, and bromodomains. Part II details specific pharmaceutical/biopharmaceutical companies and their strategies behind their target identifications and validation. These companies include Constellation Pharmaceuticals, Epizyme Inc., and EpiTherapeutics. Part III of the report covers technologies and assays available from the following biotechnology companies: Active Motif (including ChIP technology and a current list of validated antibodies), Cayman Chemical, and Reaction Biology. These sections also include interviews with CEOs and CSOs of the participating companies. The last section of the report, Part IV, gives insight into the epigenetics community. Insight Pharma Reports polled a survey which had more than 150 responses. Specific areas covered were targets under investigation, market outlook, and how partnerships have advanced the industry. vi

8 Table of Table of Executive Summary vi Part I: Epigenetic Background and Target Information 1 CHAPTER 1 What is epigenetics? 2 Histone modifications 3 Histone methyltransferases 5 Arginine methyltransferases (RMT) 5 Histone demethylases 6 Epigenetic readers 6 Part II: Targets in the Industry 10 CHAPTER 2 Constellation Pharmaceuticals 11 Company background 11 Areas of research 11 SWI/SNF 11 EZH2 12 DOT1L 12 BET bromodomains 12 Challenges encountered 13 Competitive advantage 13 Partnerships 14 Future endeavors 15 vii

9 Table of Interview with Robert Sims 16 Company background 16 Research objectives 16 Partnerships 19 Benefits and challenges 20 Future endeavors 21 CHAPTER 3 EpiTherapeutics 22 Company background 22 Areas of research 22 PLU1 22 FBXL10 23 GASC1 23 Chemistry platform 23 Challenges encountered 24 Competitive advantage 24 Partnerships and future endeavors 24 Interview with Martin Bonde 25 Company background 25 Areas of research 25 Chemistry platform 27 Challenges encountered 27 Competitive advantage 28 Partnerships 28 Future endeavors 28 viii

10 Table of CHAPTER 4 Epizyme Inc. 30 Company background 30 Areas of research 30 DOT1L 31 EZH2 32 Challenges encountered 32 Competitive advantage 32 Partnerships 33 Future endeavors 34 Interview with Jesse Smith 35 Company background 35 Areas of research 35 Target validation 36 Use of biomarkers 36 Challenges encountered 37 Partnerships 38 Future endeavors 39 Part III: Rising Technologies and Company Strategies 41 CHAPTER 5 Active Motif 42 Company background 42 Chromatin Immunoprecipitation (ChIP) technology 42 Competitive advantage 42 Challenges encountered 43 Validating antibodies using ChIP, ChIP-chip, and ChIP-Seq 43 Partnerships and strategies 54 Future endeavors 55 ix

11 Table of Interview with Kyle Hondorp 55 Company background 55 Immunoprecipitation technology 56 Challenges encountered 57 Future endeavors 58 Partnerships and growth 58 CHAPTER 6 Cayman Chemical 60 Company background 60 Applications 60 Time-resolved fluorescence resonance energy transfer (TR-FRET) assays 61 S-adenosyl-L-methionine (SAM)-screener assays 61 Challenges encountered 61 Partnerships 62 Future outlook 62 Interview with Dr. Levi Blazer, 63 Company background 63 Partnerships 63 Areas of research 63 Assays 63 Challenges encountered 64 Future endeavors 64 CHAPTER 7 Reaction Biology Corporation 66 Company background 66 Reaction Biology Corporation s role in epigenetics 66 x

12 Table of Competitive strategies 67 Future outlook 67 Interview with Haiching Ma 68 Company background 68 Areas of research 68 Partnerships 69 Future expectations 70 Part IV: Epigenetics in the Community 71 CHAPTER 8 Survey Results 72 Areas of study 73 Market outlook 74 Partnerships 75 References 76 About Cambridge Healthtech Institute 79 xi

13 Table of TABLES Table 1.1 4,5 List of known histone modifications in vertebrates 3 Table 1.2: Targets and their developmental status 7 Table 5.1: Validated antibodies using ChIP, ChIP-chip, and ChIP-Seq assays 45 FIGURES Figure 1.1: Interest in epigenetic targets over time 2 Figure 5.1: ChIP-chip validation steps 44 Figure 5.2: ChIP antibody validation steps 45 Figure 8.1: Survey demographics 72 Figure 8.2: Popular areas of study 73 Figure 8.3: Technology of choice 73 Figure 8.4: Targets of interest 74 Figure 8.5: Expected diseases to benefit from therapeutic applications 74 Figure 8.6: Classes expected to receive FDA approval 74 Figure 8.7: Participants in partnerships 75 Figure 8.8: Impact of partnerships on research 75 xii

14 Part I: Epigenetic Background and Target Information

15 Part I: What is epigenetics? CHAPTER 1 What is epigenetics? Epigenetics is a term used to describe the phenotypic changes that are not a result of changes in the nucleotide sequence of DNA. 1 Instead, these changes occur through various modifications that either suppress or activate certain genetic expressions. With epi meaning above in Greek, epigenetic traits not only allow an organism to react to their environment, but they are also passed down from one generation to the next. 2 This chapter will cover several classes currently under investigation as epigenetic modifiers. According to a PubMed conducted on October 1, 2013, histone modifications, bromodomains and epigenetic readers show increasing interest since Figure 1.1: Interest in epigenetic targets over time Growth of Interest in Histone Modifications, Bromodomains, and Epigenetic Readers Number of Title/Abstracts Source: PubMed; Date: October 1,

16 Part I: What is epigenetics? details from PubMed: (((((((((((((epigenetic target[title/abstract]) OR epigenetic targets[title/abstract]) OR histone modification[title/abstract]) OR histone modifications[title/ Abstract]) OR histone methyltransferase[title/abstract]) OR histone methyltransferases[title/ Abstract]) OR histone methylase[title/abstract]) OR histone methylases[title/abstract]) OR histone demethylase[title/abstract]) OR histone demethylases[title/abstract]) OR bromodomains[title/abstract]) OR bromodomain[title/abstract]) OR epigenetic reader[title/ Abstract]) OR epigenetic readers[title/abstract]) Histone modifications In a chromosome, DNA is tightly wrapped around many nucleosomes, which are in turn wrapped around each other for efficient packaging. 1 Nucleosomes are made up of four histones H2A, H2B, H3 and H4. These histones are in contact with the tightly wrapped DNA and their contact with certain epigenetic markers (methyltransferases, demethyltransferases, acetyltransferases, and deacetyltransferases), can alter the electrostatic nature of the chromatin or the affinity of chromatin-binding proteins, which influences the chromatin structure. 3 Histone modifications frequently occur the amino-terminal tails of the histones in one of several ways: methylation, acetylation, or phosphorylation. 4 Lysines are often modified with either acetyl or methyl groups, and at least one arginine is modified by a methyl group. Likewise, serines tend to be modified with a phosphate group. 4 By modifying these amino acids, consequences are often associated with either genetic expression or repression. 4 Table 1.1 depicts a listing of known histone modifications in vertebrates. 4,5 Table 1.1 4,5 List of known histone modifications in vertebrates Histone subunit Amino acid residue Histone modification Epigenetic result H2A Serine 1 Phosphorylation Mitosis, transcriptional repression H2A Lysine 4 Acetylation Transcriptional H2A Lysine 5 Acetylation Transcriptional H2A Lysine 7 Acetylation Transcriptional H2B Lysine 5 Acetylation Transcriptional H2B Lysine 12 Acetylation Transcriptional H2B Lysine 14 Phosphorylation Apoptosis H2B Lysine 15 Acetylation Transcriptional H3 Threonine 3 Phosphorylation Mitosis H3 Lysine 4 Acetylation, methylation Acetylation: transcriptional ; Methylation: active euchromatin 3

17 Part I: What is epigenetics? Table 1.1 4,5 List of known histone modifications in vertebrates Histone subunit Amino acid residue Histone modification H3 Lysine 9 Acetylation, methylation Epigenetic result Acetylation: transcriptional ; Methylation: H3 Serine 10 Phosphorylation Transcriptional H3 Threonine 11 Phosphorylation Mitosis H3 Lysine 14 Acetylation Transcriptional / elongation H3 Arginine 17 Methylation Transcriptional H3 Lysine 18 Acetylation Transcriptional, DNA repair H3 Lysine 23 Acetylation Transcriptional, DNA repair H3 Lysine 27 Acetylation, methylation H3 Lysine 28 Phosphorylation Mitosis Transcriptional silencing H3 Lysine 36 Methylation Transcriptional elongation H3 Lysine 56 Acetylation DNA repair Table 1.1 4,5 List of known histone modifications in vertebrates Histone subunit Amino acid residue Histone modification Epigenetic result H3 Lysine 79 Methylation Transcriptional elongation H4 Serine 1 Phosphorylation Mitosis H4 Arginine 3 Methylation Transcriptional H4 Lysine 5 Acetylation Histone deposition H4 Lysine 8 Acetylation Transcriptional H4 Lysine 12 Acetylation Histone deposition, telomeric silencing H4 Lysine 16 Acetylation Transcriptional, DNA repair H4 Lysine 20 Methylation Transcriptional silencing There are certain enzymes associated with histone modifications, specifically histone methyltransferases, histone acetyltransferases, histone demethylases, and histone deacetylases. 4 Histone methyltransferases are enzymes that add a methyl group, while demethylases are enzymes that remove a methyl group. 4 In most cases, methylation of the histone-terminal amino acids tends to repress, or silence, genetic expression; in other cases, methylation is associated 4

18 Part I: What is epigenetics? with an actively transcribed gene. 4 Methylation inhibits the binding of proteins, particularly the transcription machinery, ultimately silencing genetic expression. Acetylation, on the other hand, promotes the expression of genes by adding an acetyl group which remodels the nucleosome and histone components. 4 This reconstruction exposes DNA on the tightly wound nucleosomes to specific enzymes and allows transcription to occur. Contrasting this is histone deacetylation, which is the removal of an acetyl group. 4 When the acetyl group is removed, the nucleosomes return to their efficiently packed configuration, which inhibits transcription proteins from binding, and therefore inhibiting genetic expression. The addition and removal of methyl and acetyl groups plays a significant role in genetic expression. These groups control the exposure of DNA, either allowing or denying access of transcription groups, which ultimately decides gene expression. Because of the ability of phenotypic traits to be controlled by epigenetic factors, scientists are eager to discover what influences control these modifications, what factors are involved in recruiting methyl and acetyl groups, and why methyl and acetyl groups can both repress and activate genes. Popular targets that are being focused on include histone methyltransferases, demethyltransferases, bromodomains, and epigenetic readers. Histone methyltransferases DOT1L is a methyltransferase that has been a popular target of study because of its epigenetic link to cancer. Constellation Pharmaceuticals and Epizyme are two companies that have commented on their research with DOT1L and EZH2 and their relation to mixed-lineage leukemia (MLL). How these targets are addressed, and areas of interest, will be discussed in the company sections. Other methyltransferases under investigation include nuclear receptor SET domain-containing (NSD) proteins. This family methylates H3K36, which is a modification associated with transcription, DNA repair, and alternative splicing. 18 In addition to containing the SET domain, NSD1, 2 and 3, the three members of the NSD family, also contain PHD and PWWP domains which are important for chromatin recognition. 18 Mutations of these members of this family have been associated with different syndromes; NSD1 is mutated in Sotos syndrome, which involves developmental overgrowth and cognitive disabilities, and a small number of cytogenetically normal cases of acute myeloid leukemia (AML), where chromosomal translocation fuses the N-terminus of NUP98 to the C-terminal portion of NSD1, including the SET domain. 18 NSD3 is also mutated in rare cases of AML and increased expression of NSD3 has been seen in ~15% of breast cancers. Another histone methyltransferase mutation associated with epigenetic malfunctions is H3K9 methylation. 18 This methylation is usually associated with transcriptional repression which is related to heterochromatin formation and DNA methylation. 18 Increased levels of H3K9 have been measured in various human tumors. Also consistent with this finding is that decreased regulation of G9a (a H3K9-specific HMT) has been measured to suppress tumor cell growth and invasion in mice. Arginine methyltransferases (RMT) In addition to histone methyltransferases are arginine methyltransferases. These have also been studied (9 have been identified; PRMT1-9) and they have been associated with both positive and negative regulation of transcription. 18 Even more evidence has shown that arginine methyltransferases play a role in hematologic and solid tumors; they modify non-histone targets, affecting target gene 5

19 Part I: What is epigenetics? specificity (including p53), and their functions are affected by oncogenic pathways. 18 Histone demethylases Another type of histone modification actively studied are histone demethylases. Instead of identifying methylation that may trigger epigenetic problems, researchers are looking at the problems that can occur when groups are demethylated. CEO Martin Bonde explains EpiTherapeutics role in the epigenetic industry and how they have been focusing on several other targets including PLU1, FBXL10, and GASC1 because we believe there is strong evidence in the laboratory and also in animal experiments that these targets are good entry points if you want to stop certain cancer types. Other targets that are being investigated include LSD1, flavin adenine dinucleotide (FAD)-dependent amine oxidase, and Jumonji C ( JmjC) lysine and arginine. 18 JmjC contains two proteins of interest: UTX/UTY and JMJD3, which both play roles in demethylating the site H3K JMJD3 has been shown to display occasional mutation in cancer (the significance is unknown) and somatic loss-of-function mutations of UTX are found in 10% of multiple myelomas, 8% of esophageal squamous cell carcinomas, 1% of renal carcinomas, and occasionally in breast, AML, glioblastoma, colorectal and bladder cancers. 18 Epigenetic readers In addition to histone modifications, there are also epigenetic readers, particularly domains that influence genetic expression without changing the genome. Instead, they recognize modified forms of histone tails, working in tandem with histone modifiers. These domains include bromodomains, chromodomains, TUDOR domains, and PHD fingers. 4 Containing opposing properties is a protein domain called a SANT domain, which interacts with unmodified histone tails. 4 Epigenetic influences occur in many different forms; enzymes can be triggered by either the presence or absence of modifications. For this section, we will focus on bromodomains, a protein that recognizes acetylated histone tails, facilitating maintenance, and continuing to modify regions that have already been acetylated. 4 It has also been measured that complexes with bromodomains bind better to acetylated nucleosomes than unacetylated nucleosomes. 4 Based on these findings, scientists have concluded that a gene carrying acetylated nucleosomes at its promoter will have a much higher affinity for transcriptional machinery, and therefore promoting gene expression, than a gene with unacetylated nucleosomes. 4 6

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