7:00 am Registration & Networking Coffee

8:20 am Chair’s Opening Remarks

  • Jane Withka Director & Collaboration Lead, Pfizer Worldwide R&D

Drugging the Undruggable RNA: Expanding the Knowledge of RNA Structure, Function & Role in Disease

8:30 am Structure-Based Discovery of New Functions in Large RNAs

  • Kevin Weeks Founder of Ribometrix; Professor of Chemistry, University of North Carolina


• New technologies enable discovery of functional RNA structures
• Focusing on complex 3D RNA structures offers a compelling approach for drug discovery

9:00 am MicroRNA-Based Therapeutics in Cancer

  • Frank Slack Co-Founder of Twentyeight- Seven Therapeutics; Professor of Pathology, Beth Israel Deaconess Medical Center


• Learn about the connection of microRNAs and cancer
• Learn about delivery of microRNAs as therapeutics
• Learn about mouse models of microRNA over-expression Julius B.

9:30 am Nascent RNA Structures: A Potential Gold Mine for Drug Targets


• RNAs fold dynamically every time they are synthesized in the cell during transcription
• There appear to be general principles that govern RNA cotranscriptional folding pathways such as the prevalence of kinetically trapped out-of-equilibrium folded states
• These states may be ideal targets for small molecule drugs that can trap RNAs and disrupt their function

10:00 am Speed Networking & Morning Refreshments

The Era of Epitranscriptomics: Successfully Targeting RNA via Interfering with RNA-Protein Interactions

11:00 am Emerging Role of RNA Methylation in Cancer

  • Richard Gregory Co-Founder of Twentyeight- Seven Therapeutics; Professor, Boston Children’s Hospital/Harvard Medical School


• Our focus is on understanding the mechanisms and role of RNA methylation in cancer
• Of particular relevance is our recent breakthrough findings that provide the very first functional evidence linking the N6-methyladenosine (m6A) modification of mRNAs with cancer and provides the first insights into the role and mechanism of the m6A methyltransferase METTL3 in the control of oncogene mRNA translation
• Our lab uncovered the very first m6A epitranscriptome in human tumor samples and our pioneering studies pave the way for the emergence of the epitranscriptome and cancer field
• We also developed new methods to map the N7-methylguanosine (m7G) modification of tRNAs by METTL1 and will present our latest findings on the role of METTL1 in oncogenic transformation

11:30 am Drugging RNA Modifying Enzymes


• An outline of the progress made by Storm in drugging RNA modifying enzymes
• This will include the technologies we are utilizing and the supporting data
• An update on our latest progress

12:00 pm RMP-Targeted Cancer Drug Discovery


• RNA modifying proteins (RMPs) represent a large class of novel targets for oncology and other disease indications that can be targeted with small molecule inhibitors
• Accent has prioritized drug discovery efforts on METTL3, an m6A RNA methyltransferase implicated in AML and multiple solid tumor indications
• Potent, selective inhibitors of METTL3 have been identified and characterized in biochemical and cellular assays with correlations seen between biochemical potency, m6A depletion and cell proliferation

12:30 pm Epitranscriptomic ‘m6A’ Target Space: When & Why to go Biophysical with Your Target


• Small-molecule drug discovery projects are pursued within Gotham
• Inhibitors and Antagonists for m6A-writing and -erasing enzymes, as well as for reader domains are being developed
• Intensive use of complementary biophysical techniques such as SPR, Xray, protein NMR allows for deeper understanding of exact molecular mechanisms of action, and thus provides the rationales for choosing best possible chemical matter

1:00 pm Networking Lunch

Advancing Identification & Validation of Viable RNA Target Sites for Therapeutic Intervention

2:00 pm Targeting Non-Coding RNAs with Small Molecules: From Theory to Medical Practice

  • George A. Calin Professor, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center


• Why targeting non-coding RNAs with small molecules?
• Who are the patients to be targeted?
• What are the non-coding RNAs to be targeted?

2:30 pm Identifying Inhibitors of Dicer Processing of Specific Pre-miRNA Motifs


• Small non-coding RNA molecules such as microRNA play key roles in the regulation of many essential biological processes making them intriguing targets for therapeutic intervention
• Dicer endonuclease processing of pre-microRNA to mature miRNA is a potential node for modulation of gene silencing, but the essential activity of Dicer and the small size and minimal tertiary structure of specific pre-miRNA make them difficult targets for rational drug design strategies
• We are developing new methods for identifying and characterizing inhibitors of processing of specific pre-miRNA sequences by Dicer

3:00 pm Targeting Pre-mRNA Splicing to Discover Novel Small Molecule Therapeutics


• snRNP recruitment and splice site recognition is driven by RNA-RNA interactions and forms the basis of pre-mRNA splicing
• The diversity of sequences found at splice sites throughout the human genome provide unique potential drug targets and have led to the discovery of small molecule splicing modifiers for clinical use in genetic diseases such as spinal muscular atrophy and familial dysautonomia
• Based on this work, we have built platform technologies that enable the discovery of additional splicing modifiers for therapeutically relevant splicing events

3:30 pm Afternoon Refreshments & Networking

4:00 pm Unlocking RNA Biology: Platform to Study RNA-Protein Interactions to Identify Novel Targets for Small Molecule Discovery

  • Pramod Pandey Principal Scientist, Merck Research Labs Exploratory Science Center


• A large fraction of the genome is transcribed into non-coding RNAs and many of these have been implicated in influencing diseases
• We are studying these in the context of diseases, relating to barrier function/ dysfunction
• Towards that goal, we are developing chemical biology tools to study the RNAprotein interactions and find novel targets for small molecule drug discovery

4:30 pm Exploration of Fragment Ligand Binding at a Viral Noncoding RNA Target

  • Thomas Hermann Professor of Chemistry & Biochemistry; Associate Dean of Physical Sciences, University of California, San Diego


• Conserved noncoding RNA motifs in viral genomes provide opportunities as targets for the development of viral inhibitors with a high barrier to resistance development
• I will discuss the discovery of a target for viral translation inhibitors in the internal ribosome entry site (IRES) RNA of the hepatitis C virus (HCV)
• A structure-guided approach was used to discover drug-like fragments for the development of antiviral compounds

5:00 pm Structure- & Fragment-Based Development of Small Molecules Targeting RNA-Modifying Proteins & Protein-RNA Interactions Involved in Epitranscriptomic Regulation

  • Pawel Sledz Senior Scientist & Project Manager, University of Zurich


• Covalent post-transcriptional modifications of RNA by RMPs constitute additional layer of gene expression regulation; malfunctions of this machinery have been implicated in cancer
• Epitranscriptomic modifications alter the properties and dynamics of modified transcripts and expose them to modification-dependent protein-RNA interactions (PRI) with different reader proteins
• We demonstrate that both RMPs and PRIs involved in epitranscriptomics modifications can be targeted with small molecules; their early development will be discussed

5:30 pm Chair’s Closing Remarks & End of Day One