Cambridge Healthtech Institute’s 5th Annual

Small Molecules Targeting RNA

Identifying New Drug Modalities and RNA Moieties for Therapeutic Intervention

September 26 - 27, 2023 EDT

Using small molecules to modulate RNA binding and function and get the desired biological outcome has generated much interest in drug discovery. However, understanding the structure and function of various RNA moieties present in the cell and the proteins they interact with-- and then identifying which one to target and how to target it has not been that easy. Challenges also exist in terms of determining the in vivo specificity, selectivity, and safety of these new small molecule modalities. Cambridge Healthtech Institute's conference on Small Molecules Targeting RNA will highlight some of the innovative approaches being pursued to identify and modulate the right RNA target.

Tuesday, September 26

Registration and Morning Coffee7:00 am

Welcome Remarks7:55 am

TOOLS FOR RNA DRUG DISCOVERY

8:00 am

Chairperson's Remarks

Susanne Swalley, PhD, Principal, Aspen Point Consulting LLC

8:05 am

Chemical Strategies for Profiling RNA-Protein Interactions

Ken Hsu, PhD, Stephen F. and Fay Evans Martin Endowed Associate Professor, Department of Chemistry, The University of Texas at Austin

We present a method that deploys clickable probes to directly quantify protein-RNA interactions on proteins. Our method facilitated global detection of RNA-interaction sites on RBPs that mediate recognition of coding and noncoding RNA. We performed functional profiling of known RNA-binding interfaces and discovery of RNA binding activity on proteins without prior RBP annotation. Collectively, we present a chemoproteomic method for systematic quantification of protein-RNA binding activity in living cells.

8:35 am

Synthetic Biology Approaches to Measure and Control RNA

Bryan Dickinson, PhD, Assistant Professor, Department of Chemistry, University of Chicago

Especially in mammalian systems, post-transcriptional gene expression regulatory processes at the RNA level are often a key determinant of genetic information flow. From an engineering and therapeutic perspective, these RNA regulatory processes represent new ways to control or retune gene expression at the RNA level, if they can be harnessed. I will present technologies our group has developed to measure and control protein-RNA interactions with an eye toward therapeutic development.

9:05 am

Structure-Based RNA-Ligand Design: Pitfalls and Solutions

Christian Kersten, PhD, Assistant Professor, Institute of Pharmaceutical & Biomedical Sciences, Johannes Gutenberg University, Mainz

Targeting RNA with small molecules is an emerging field. However, screening strategies usually rely on HTS, FBDD or derivatization of a known ligand while structure-based design is still the exception. In our work we demonstrate the suitability of (modified) protein-based docking tools for RNA targets and highlight special caveats. In a subsequent prospective virtual screening against the preQ1-riboswitch, 6 novel ligands with affinities between 30nM and 11µM were identified.

Networking Coffee Break9:35 am

10:05 am

Application of Artificial Intelligence for the Discovery of RNA-Targeting Small Molecules

Sridhar Narayan, PhD, Vice President, ReviR Therapeutics

Modulating RNA with small molecules could dramatically expand the universe of druggable targets. However, properties such as low diversity, a charged backbone, and dynamic structure make targeting RNAs challenging compared to protein targets. Moreover, standard biophysical and structural biology techniques have not directly translated from the protein world. Here, I present several Artificial Intelligence (AI) tools that we are utilizing to overcome some of these challenges in RNA drug discovery.

10:35 am

Mapping the Druggable Transcriptome: AI-Enabled RNA Drug Discovery 

Rabia Khan, PhD, MBA, CEO, Serna Bio

An estimated 85% of the ~3 billion base pairs in the human genome is transcribed into RNA, but only ~1.5% of these code for proteins. While the chemical properties of protein binders are increasingly understood and interrogated, the field of RNA-targeted drugs is relatively new and the properties of small molecules that drive specific and selective targeting of RNA, and associated assays, are yet to be developed. At Serna Bio (previously Ladder Therapeutics) we are using an AI enabled, data-first approach to write the rules that define RNA-small molecule interactions.

11:05 am

Unlocking the Druggable Universe of 3D RNA Structures with Artificial Intelligence

Adrian Sanborn, PhD, Founding Scientist & Bioscience Lead, Atomic AI

Atomic AI has developed PARSE, the Platform for AI-driven RNA Structure Exploration, which can locate 3D structures at unprecedented speed and accuracy in disease-relevant RNA targets. PARSE builds on our work featured on the cover of Science, and involves a tight integration of high-throughput wet-lab experiments and cutting-edge artificial intelligence capabilities. Through this data-driven approach, Atomic AI is enabling and pursuing drug discovery against undruggable targets.

11:35 am Discovery of RNA Targeting Small Molecules: Our Toolbox for RNA Drug Discovery

Wenji Su, PhD, Senior Director and the Head of Early Discovery Platform, WuXi Biology, WuXi AppTec

RNA-as-a-target holds the promise of dramatically increasing the pool of druggable targets. “DNA-Zipper” DEL technology reduces interference between DNA tags and RNA molecules, addressing a key hurdle in screening scalability when targeting RNA with small molecules.  Here, we demonstrate the successful application of Zipper DEL and SHAPE-MaP to identify ligands that bind to SMN2. Validation and functionality of this binding was then determined using SPR, ASMS, biochemical, and cellular assays.

Enjoy Lunch on Your Own11:50 am

RNA TARGETING STRATEGIES

1:15 pm

Chairperson's Remarks

Rabia Khan, PhD, MBA, CEO, Serna Bio

1:20 pm

FEATURED PRESENTATION: Structure-Based Design of Small Molecule Inhibitors of RNA

Jennifer Petter, PhD, Founder & CSO, Arrakis Therapeutics

Our mission at Arrakis is to solve very broadly the problem of how to drug RNA with small molecules. This presentation will provide an update on the platform we have built to achieve that mission and provide early data on specific mRNA targets.

2:20 pm Accelerating Cell and Gene Therapy CMC programs – SGS’s Analytical Arsenal

Robert Cartee, PhD, Senior Director, Biopharmaceutical Services, Health & Nutrition, SGS

Gene therapy products are becoming powerful tools for the treatment of a variety of diseases including genetic syndromes and cancers. These products require sensitive and reproducible methods to evaluate their identity, purity, safety and potency. In this presentation, we will be discussing:   

  • Current regulatory perspectives on gene therapy product quality assessment from preclinical through Phase 3
  • Analytical portfolio required to assess gene therapy product quality

In-Person Group Discussions2:50 pm

In-Person Group Discussions are informal, moderated discussions, allowing participants to exchange ideas and experiences and develop future collaborations around a focused topic. Each discussion will be led by a facilitator who keeps the discussion on track and the group engaged. To get the most out of this format, please come prepared to share examples from your work, be a part of a collective, problem-solving session, and participate in active idea sharing. Please visit the In-Person Group Discussions page on the conference website for a complete listing of topics and descriptions.

IN-PERSON GROUP DISCUSSION 3A:

Challenges and Opportunities in Pursuing RNA as a Drug Target

Brahma Ghosh, PhD, Senior Principal Scientist & Head, Chemical Biology, Global Discovery Chemistry, Janssen Research & Development, LLC

Rabia Khan, PhD, MBA, CEO, Serna Bio

Jennifer Petter, PhD, Founder & CSO, Arrakis Therapeutics

Alexander Serganov, PhD, Associate Professor, Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine

  • Emerging techniques for probing and modulating RNA
  • Co-relating RNA binding with function and physiological response
  • Rules for designing focused chemical libraries for targeting RNA/RNA-binding proteins
  • Designing and optimizing small molecules targeting various RNA moieties
  • Leveraging AI/ML, RNA degradation tools, and other drug development strategies​

Grand Opening Refreshment Break in the Exhibit Hall with Poster Viewing3:35 pm

4:15 pm

FEATURED PRESENTATION: Tools to Measure RNA binding Protein-RNA Defects 

Eugene Yeo, PhD, MBA, Professor, Cellular and Molecular Medicine, University of California, San Diego; Founding Member, Institute for Genomic Medicine

I will discuss transcriptome-wide methods we have developed to assess defects and RNA binding protein-RNA changes in small molecule-mediated perturbation of systems.

4:45 pm

Discovery of Covalent Small Molecules Targeting the RNA-Binding Protein NONO

Brahma Ghosh, PhD, Senior Principal Scientist & Head, Chemical Biology, Global Discovery Chemistry, Janssen Research & Development, LLC

Here I will report on the chemoproteomics-driven discovery of small-molecule modulators targeting the RNA-binding protein NONO with a functional consequence. By engaging Cys145 of NONO, these electrophilic compounds decrease transcripts encoding the androgen receptor and its V7 splice variant in human prostate cancer cells in a stereoselective fashion. Our findings demonstrate that NONO can be co-opted by covalent small molecules to rewire the transcriptional state of cancer cells.

5:15 pm

RNA-Small Molecule Interactions: Lessons Learned from Riboswitch Structures

Alexander Serganov, PhD, Associate Professor, Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine

This talk illustrates the adaptability of small molecule recognition by RNA using ykkC riboswitches that use a similar mRNA structure to recognize very different small molecules. I will discuss our current efforts of structure-based design of synthetic small molecules to bind to thiamine pyrophosphate riboswitch and serve as potential anti-bacterials.

Welcome Reception in the Exhibit Hall with Poster Viewing5:45 pm

Close of Day6:45 pm

Wednesday, September 27

Registration and Morning Coffee7:30 am

NEW mRNA MODULATORS

7:55 am

Chairperson's Remarks

Pedro Serrano Navarro, PhD, Senior Director, Takeda

8:00 am

Discovery of Small Molecules Regulating mRNA and Identification of Novel mRNA Regulatory Target Proteins

Iris Alroy, PhD, Co-Founder & CSO, Anima Biotech

The mRNA Lightning™ platform integrates mRNA biology and AI to identify small molecules that modulate mRNA regulation and novel mRNA biology targets. We have identified compounds that effectively target NSCLC over expressing c-Myc protein and Idiopathic Pulmonary fibrosis by involving novel mRNA regulatory proteins that work through distinct mechanisms including splicing, RBP modification, RBP modifications, and regulation of mRNA recruitment to polyribosomes.


8:30 am Magnetic Force Spectroscopy: Improving ‘Hit-to-Lead’ & ‘Lead Optimization’ in RNA-Targeted Small-Molecule Drug Discovery

Gordon Hamilton, PhD, President & CEO, Depixus SAS

Progress in targeting RNA is limited by a lack of effective methods to visualize and understand how RNA structures interact with their native ligands and candidate drugs.  Based on magnetic force spectroscopy, MAGNA™ offers a powerful new way to accurately probe these interactions.  Using data on binding kinetics and concentration-dependency, we show how MAGNA™ provides valuable insights for ‘hit-to-lead’ and ’lead optimization’ for RNA-targeted therapeutics to de-risk and accelerate drug development.

9:00 am

Small Molecules Modulating ELP1 mRNA for Potential Use in Treatment of Familial Dysautonomia

Marla Weetall, PhD, Senior Vice President, Pharmacology and Biomarkers, PTC Therapeutics

 Familial dysautonomia (FD) is a rare neurodevelopmental and neurodegenerative disease associated with autonomic and sensory neuropathy. Over 99% of FD patients are homozygous for the “founder" mutation in intron 20 of the ELP1 gene (c.2204 + 6T > C) causing the “skipping” of exon 20 from the mature mRNA coding sequence. Here, we describe the discovery and development of small molecules that modulate the splicing of the mutant ELP1 RNA.  We utilize mouse models of FD to correlate drug levels to corrected splicing, increased protein levels, and improved phenotype. We discuss how these data can be used to better design clinical trials testing splicing modulators.

9:30 am

Small Molecule Correctors of Aberrant ELP1 pre-mRNA Alternative Splicing: Discovery, Development, and Mechanism

Scott Barraza, PhD, Group Leader, Discovery Chemistry, PTC Therapeutics Inc.

Familial dysautonomia is a debilitating neurodegenerative disorder arising from aberrant mutation-linked alternative splicing of ELP1 pre-mRNA. Treatment is limited to palliative care, however, due to the absence of effective etiology-targeted therapies. Addressing this issue, PTC Therapeutics has developed potent small molecule splicing modulators based on hits originally identified by collaborative partners at Massachusetts General Hospital. Their discovery and putative pharmacological mechanism of action is described.

Coffee Break in the Exhibit Hall with Poster Viewing10:00 am

PLENARY KEYNOTE PROGRAM

10:40 am

Plenary Chairperson’s Remarks

An-Dinh Nguyen, Team Lead, Discovery on Target, Cambridge Healthtech Institute

10:45 am

PLENARY: The New Science of Therapeutics

Jay E. Bradner, MD, Physician Scientist, Former President, Novartis Institutes for BioMedical Research, Inc.

I will share reflections on how new paradigms in the science of therapeutics are creating opportunities to approach historic challenges in medicine. Specifically, I will share approaches to targeting transcription factors and discuss how modularity is a paradigm for next-generation low-molecular weight and biological therapeutics. Finally, I will offer reflections on drug development and the fitness, opportunities, and challenges of the biomedical ecosystem.

11:30 am

PLENARY: Accelerating Drug Discovery Using Machine Learning and Cell Painting Images

Anne E. Carpenter, PhD, Senior Director, Imaging Platform & Institute Scientist, Broad Institute

Shantanu Singh, PhD, Senior Group Leader, Machine Learning, Imaging Platform, Broad Institute

Microscopy images can reveal whether a cell is diseased, is responding to a drug treatment, or whether a pathway has been disrupted by a genetic mutation. In a strategy called image-based profiling, often using the Cell Painting assay, we extract hundreds of features of cells from images. Just like transcriptional profiling, the similarities and differences in the patterns of extracted features reveal connections among diseases, drugs, and genes.

Close of Small Molecules Targeting RNA Conference12:15 pm