Cambridge Healthtech Institute’s Inaugural

RNA as a Small Molecule Target
( 作为小分子药物标靶的RNA )

Expanding the Boundaries of Druggable Targets


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 Small Molecule Target symposium, part of Drug Discovery Chemistry, as we discuss methods and tools to identify specific, potent, novel, small molecule binders of RNA.

Final Agenda


7:30 am Registration Open and Morning Coffee


7:55 Welcome and Opening Remarks

Mana Chandhok, Conference Producer, Cambridge Healthtech Institute

Amanda Hargrove, PhD, Assistant Professor of Chemistry, Duke University

8:00 Targeting Structurally and Functionally Diverse RNAs with Drug-Like Small Molecules

John SchneeklothJohn Schneekloth Jr. (Jay), PhD, Senior 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.

8:30 Repurposing Tools for RNA – And What to Consider When Doing It

Jenifer KaplanJenifer Kaplan, PhD, Scientist II, Biophysics and Assay Development, Arrakis Therapeutics

The identification of drug-like small molecule medicines that directly bind to RNA and modulate its biological function will vastly increase our therapeutic target space, but targeting RNA comes with its own inherent challenges. The ensemble of conformations an RNA can adapt needs to be forefront when interpreting the results of biophysical and biochemical assays. We use a combination of repurposed tools to characterize the binding event and gain insight into how the ligands are interacting with the RNA target.

9:00 Deciphering Patterns in Selective Small Molecule:RNA Interactions

Amanda HargroveAmanda Hargrove, PhD, Assistant Professor of Chemistry, Duke University

To gain fundamental insights into drivers of selectivity in small molecule:RNA recognition, we analyzed patterns in RNA-biased small molecule chemical space to reveal distinct physicochemical, structural, and spatial properties for selective RNA ligands. We further used pattern recognition protocols to identify RNA topologies that can be differentially recognized by small molecules. These insights have led to improved recognition of medicinally relevant RNA targets, including viral and long noncoding RNA structures.

9:30 Networking Coffee Break


10:00 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.

10:30 Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 (SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA)

Hasane Ratni, PhD, Expert Scientist, Medicinal Chemistry, F. Hoffmann-La Roche, Basel, Switzerland

SMA is an inherited disease that leads to loss of motor function and ambulation, and a reduced life expectancy. We have been working to develop orally-administrated, systemically-distributed small molecules to increase levels of functional SMN protein. Herein, we describe the discovery risdiplam that focused on thorough pharmacology, DMPK and safety characterization and optimization. This compound is completing pivotal clinical trials and is a promising medicine for the treatment of patients in all ages and stages of SMA.

11:00 Sponsored Presentation (Opportunity Available)

11:15 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:00 pm Session Break


1:00 Chairperson’s Remarks

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

1:05 Discovering Novel RNA-Binding Proteins for Small Molecule Drug Discovery

Pramod PandeyPramod Pandey, PhD, 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 RNA protein interactions and find novel targets for small molecule drug discovery.

1:35 RNA Splicing Modulation… Application to CD33

Tom ChappieTom 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.

2:05 CO-PRESENTATION: Paving the Way for the Discovery of Small-Molecule Drugs Targeting the mRNAVeritas_In_Silico

Morishita_EllaElla Morishita, PhD, Senior Investigator, Basic Research Division, Veritas In Silico

Nakamura_ShingoShingo Nakamura, PhD, CEO, Veritas In Silico

The potential of targeting mRNAs with small molecules has been unlocked, but the path that would lead to their discovery remains unclear. We are finding druggable motifs on any given mRNA and discovering small molecules targeting them using our ibVIS-SMD platform, which combines informatics with biophysical and cellular biology approaches. Here, we will describe how the ibVIS-SMD platform enables target identification, tailored screening of chemical libraries, hit validation, and structure-based lead optimization.

2:35 Networking Refreshment Break


3:05 Drugging RNA

Natalie Dales, PhD, Director, Global Discovery Chemistry, Novartis

3:35 FIRESIDE CHAT: What Lies Ahead?

Hasane RatniHasane Ratni, PhD, Expert Scientist, Medicinal Chemistry, F. Hoffmann-La Roche, Basel, Switzerland

How will targeting RNA revolutionize drug discovery? Are there specific technologies that will help bring this around?

4:05 Successes and Challenges in Targeting RNA with Small Molecules

Nathan BairdNathan Baird, PhD, Interim Chair, Department of Chemistry & Biochemistry, Associate Professor of Biochemistry, University of the Sciences

Efforts targeting RNA with small molecules have been deterred by the inherent propensity of structured RNA molecules to adopt multiple conformations. The Baird Lab works to take direct advantage of RNA structural flexibility to discover small molecule inhibitors of RNA by simultaneously evaluating RNA structures and chemical screens. Our results demonstrate that targeting non-functional RNA structures is a challenging yet effective approach for therapeutic development.

4:35 Close of Symposium

* 活动内容有可能不事先告知作更动及调整。

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