RNA molecules are crucial for delivering cellular information and genetic regulation, but until recently, the drug discovery world has emphasized protein drug targets. Our lack of knowledge in RNA biology prevented us from exploring possibilities of RNA
drug targets, but with recent advances in technologies such as sequencing, new therapeutic strategies are being explored. Join us at the Inaugural RNA as a Drug Target conference, part of Discovery on Target, as we discuss RNA as a novel target site
for therapeutics.
Final Agenda
Wednesday, September 18
11:20 am Conference Registration Open (America Foyer)
12:20 pm Event Chairperson’s Opening Remarks
An-Dinh Nguyen, Team Lead, Discovery on Target 2019, Cambridge Healthtech Institute
12:30 Plenary Keynote Introduction
Anjan Chakrabarti, Vice President, Discovery Chemistry, Syngene International Ltd
12:40 Base Editing: Chemistry on a Target Nucleotide in the Genome of Living Cells
David R. Liu, PhD, Howard Hughes Medical Institute Investigator, Professor of Chemistry & Chemical Biology, Harvard University
1:20 PROTACs: Past, Present, and Future
Craig M. Crews, PhD, Professor, Chemistry; Pharmacology; Molecular, Cellular & Developmental Biology; Yale University
2:00 Close of Plenary Keynote Program
2:00 Dessert Break in the Exhibit Hall with Poster Viewing (America Ballroom)
2:45 Organizer's Welcome Remarks
2:50 Chairperson’s Opening Remarks
Meizhong Jin, PhD, Senior Director, Chemistry, Arrakis Therapeutics
2:55 FEATURED PRESENTATION: Non-Coding RNA as a Small Molecule Drug Target
Elliott Nickbarg,
PhD, Principal Scientist, Pharmacology Department, Merck & Co, Inc.
To understand RNA-small molecule druggability, we have validated an affinity-selection mass spectrometry screening system for detection of RNA-small molecule interactions. This system was used to screen a variety of RNA targets against diverse small molecule
collections, functionally annotated compounds, and collections enriched in RNA-binding properties. The system generated a large dataset of small molecule-ncRNA interactions. Here, we outline our approach and results, and discuss implications for new
drug discovery efforts.
3:25 Directly Targeting RNA with Small Molecules
Meizhong Jin, PhD, Senior Director, Chemistry, Arrakis Therapeutics
RNA plays critical roles in gene expression and regulation and, as such, RNA molecules are implicated human disease, often via the undruggable proteins expressed by those RNAs. RNA as a therapeutic target has been validated clinically by oligonucleotide
drugs although with limitations. Recent advances in RNA structure and biology point to the exciting potential of directly targeting RNA with drug-like small molecules, offering potential advantages over oligonucleotides.
3:55 Inducing the Biogenesis of Mir-124 by the Drug Candidate ABX464 Opens a Novel Way to Treat Inflammatory Diseases
Jamal Tazi, PhD, Vice President, Research, ABIVAX; Director, Cooperative Laboratory ABIVAX-CNRS
ABX464 is a first-in-class, clinical-stage, small molecule for oral administration that has shown strong anti-inflammatory effects in patients with moderate to severe Ulcerative Colitis. ABX464 binds to the cap binding complex (CBC) leading to enhancement
of the splicing of a single long noncoding RNA to generate the anti-inflammatory miR-124 in patients. The specific ability of ABX464 to generate anti-inflammatory miR-124 may pave the way of a safe and efficient treatment in several inflammatory diseases.
4:25 Refreshment Break in the Exhibit Hall with Poster Viewing
5:00 Precise and Potently Bioactive Small Molecules Interacting with RNA (SMiRNAs)
Suzanne
Rzuczek, PhD, Associate Scientific Director, Expansion Therapeutics
The expanding role of RNA in disease has led to exploring RNA as a drug target; however, the ability to selectively target RNA remains challenging. We have assembled technologies and tools to facilitate the identification of specific and potent novel
small molecule binders of RNA. We will highlight this generally applicable technology to the design and study of potently bioactive and selective SMiRNAs targeting CUG repeats in Myotonic Dystrophy Type 1 (DM1).
5:30 Targeting Structurally and Functionally Diverse RNAs with Drug-Like Small Molecules
John S. Schneekloth Jr. (Jay), PhD, Principal Investigator, Chemical Biology Laboratory; Head, Chemical Genetics Section, Center for Cancer Research, National Cancer Institute, NIH
The past twenty years have seen an explosion of interest in the structure and function of RNA and DNA. While some 80% of the human genome is transcribed into RNA, just ~3% of those transcripts code for protein sequences. Here we discuss our group’s
efforts to target RNA and DNA with drug-like small molecules using a Small Molecule Microarray (SMM) screening platform and the molecular basis for these interactions.
6:00 Targeting Pre-mRNA Splicing with Small Molecules
Marla Weetall,
PhD, Vice President, Pharmacology, PTC Therapeutics
Pre-mRNA splicing is emerging as a key control point in the expression of disease-modifying genes. Mutations causing alterations in splicing may result in diseases. Small molecules that affect pre-mRNA splicing have been identified and are being clinically
developed. At PTC, we have developed a general approach to discover and develop drugs targeting splicing. Here we describe the application of this approach to spinal muscular atrophy, familial dysautonomia, and Huntington’s disease.
6:30 Dinner Short Course Registration (America Foyer)
Click here for details on short courses offered.
9:30 Close of Day
Thursday, September 19
7:00 am Registration Open (America Foyer)
Essex Ballroom
7:30 Interactive Breakfast Breakout Discussion Groups - View All Breakoutsxxxxxxxxxxxxxxxxxxxxxxx
Grab a cup of coffee and join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop
future collaborations around a focused topic.
What Happens When You Get Off-Target Effects?
Moderator: Arthur A. Levin, PhD, Executive Vice President, R&D, Avidity Biosciences
- How are off-target events for RNA-targeting drugs being avoided and assessed?
- What approaches are being taken to broaden delivery, the major hurdle for RNA-targeting therapeutics?
- After delivery what is the next challenge for RNA-targeting drugs?
Predictiveness of Animal Models
Moderator: Marla Weetall, PhD, Vice President, Pharmacology, PTC Therapeutics
- Discussion will revolve around using animal models to predict safety and efficacy as many splicing sites are not conserved across species
8:30 Transition to Sessions
8:40 Chairperson’s Remarks
Razvan Nutiu, PhD, Investigator, Chemical Biology & Therapeutics, Novartis
8:45 Translation Control Therapeutics
Kevin Pong, PhD, Vice President, Business Development, Anima Biotech, Inc.
Anima Biotech is advancing Translation Control Therapeutics, the first platform for the discovery of small molecule drugs that specifically control mRNA translation as a new strategy against many diseases. With novel biology that monitors the
translation of proteins and proprietary cloud-based analysis software, we identify drug candidates that modulate a target protein’s production. We develop a pipeline across therapeutic areas and partner with Pharma for their targets
including our +$1B collaboration with Lilly. Our approach was further validated with 5 granted patents, 14 peer reviewed publications and 17 scientific collaborations.
9:15 RNA Splicing Modulation… Application to CD33
Tom Chappie, Associate Research Fellow, Pfizer
GWAS studies on large populations of patients with late-onset Alzheimer’s Disease have identified a SNP in the innate immune-response receptor CD33 (Siglec 3) that is protective for Alzheimer’s disease. This protective SNP is hypothesized
to induce an exon skipping event in the translation of CD33 protein. A phenomimetic strategy for hit identification of small molecule splicing modulators will be described.
9:45 Modulating the
Epitranscriptomic RNA Modifications for Cancer Therapy - Targeting
METTL3/METTL14 complex
Pawel Sledz, PhD, Senior Scientist, Department of Biochemistry, University of Zurich
The modifications of transcriptomic RNA (also called epitranscriptomic modifications) have recently emerged as mechanism of regulation of gene expression, and due to implication in a number of diseases have attracted attention of the drug discovery
community. We have pioneered early discovery in epitranscriptomic target space focusing on modulating RNA-modifying proteins (RMPs) and protein-RNA interactions (PRIs), and delivered lead candidates in two programs. In my talk I
will discuss the challenges and opportunities in this target space, as well as provide update on our portfolio: lead generation (focusing on structure- and fragment-based development of METTL3/METTL14 inhibitors), preclinical studies, and
drug-discovery platform.
10:15 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced (America Ballroom)
10:55 Enabling Modulation of RNA Biology in Human Disease with Small Molecules
Razvan Nutiu, PhD, Investigator, Chemical Biology & Therapeutics, Novartis
RNA biology is relevant to human disease and drug discovery. To enable drug discovery in the RNA space, several key challenges have to be addressed: what are the most relevant RNA biology phenotypes that affect human disease? What are the molecular
interactions that control these phenotypes? What is the chemistry capable of modulating relevant RNA structures and/or RNA/protein complexes? The presentation aims to discuss some of these challenges and to propose an integrated approach to
RNA targeted drug discovery using small molecules.
11:25 FEATURED PRESENTATION: Structure-Based Discovery of New Functions in Large RNAs
Kevin Weeks, PhD, Kenan Distinguished Professor of Chemistry, University of North Carolina
The functions of many RNA molecules – including mRNAs, long non-coding RNAs, and the genomes of RNA viruses – require that an RNA fold back on itself to create intricately and complexly folded structures. This talk will focus on recent
progress in our lab with high-resolution RNA structure probing over large scales such that both secondary and tertiary structure elements can be identified and such that these structural data can be used to identify RNA elements likely to
have direct and important roles in cellular function and gene regulation.
11:55 Biophysics-Based Drug Discovery for Epitranscriptomics: Fragment Derived Inhibitors of METTL3/METTL14
Stijn Gremmen, Head, Chemistry, ZoBio
Modulation of enzymes that modify RNA (epitranscriptomics) is gaining interest in drug discovery. Gotham Therapeutics and ZoBio are developing inhibitors of METTL3/METTL14, a SAM-dependent methyltransferase that modifies adenosine in mRNA to generate
m6A and thereby regulates protein expression. Results from fragment screening and hit evolution that have enabled understanding of the mode of action at atomic resolution will be presented. ZoBio is now well positioned to generate in vivo inhibitors that will further Gotham’s programs.
12:25 pm Enjoy Lunch on Your Own
1:25 Refreshment Break in the Exhibit Hall with Poster Viewing
2:05 Chairperson’s Remarks
Arthur A. Levin, PhD, Executive Vice President, R&D, Avidity Biosciences
2:10 Oligonucleotide Therapeutics Now on Target: Advances in Antibody Oligonucleotide Conjugates (AOCs)
Arthur A. Levin,
PhD, Executive Vice President, R&D, Avidity Biosciences
The ability to utilize genomic information to design oligonucleotide therapeutics is the goal of the industry. Their broader potential as therapeutics has remained untapped because delivery to cells is limited. We are utilizing monoclonal antibodies
against internalized cell surface proteins as a delivery mechanism for oligonucleotide therapeutics. We have developed a technology that allows us to successfully delivery oligo payloads to multiple cell types.
2:40 Cooperative RNA Modulation to Improve Iron Homeostasis Specific to Neurons while Providing Anti-Amyloid Efficacy as a Potential Alzheimer’s Disease Therapy
Jack Rogers, PhD,
Director of Neurochemistry Laboratory, Associate Professor (HMS), Harvard University; Director of Neurochemistry Massachusetts General Hospital
The project describes an active collaboration between Drs. Jack Rogers, Catherine Cahill, Xudong Huang, Debomoy Lahiri to pursue RNA mediated therapies with the neurotrophin BL-1. This agent represses neuronal Prion Protein (anti amyloid), activates
neuronal iron storage in ferritin and it can inhibit phosphoryation of the neurofibrillary associated tau protein.
3:10 PATrOL-Enabled Therapies Targeting Mutant RNA Primary and Secondary Structures
Letha Sooter, PhD, VP of Biology and Bioinformatics, NeuBase Therapeutics, Inc.
NeuBase is developing next-generation gene silencing therapies with a flexible, highly specific synthetic antisense technology. The proprietary peptide-nucleic acid (PNA) antisense oligonucleotide (PATrOL™) platform allows for the rapid
development of targeted drugs, increasing the treatment opportunities for the hundreds of millions of people affected by rare genetic diseases, including those that are impossible to treat using traditional antisense approaches. Using PATrOL
technology, NeuBase aims to first tackle rare, genetic neurological disorders.
3:40 PANEL DISCUSSION: What Have We Learned and Where Do We Go?
4:10 Close of Conference