SC6: RNA as a Small Molecule Drug Target
Monday, September 19 | 12:00 - 3:00 pm

About the Course:

Long considered a molecule that existed simply to transmit information for coding proteins, it has become clear that RNA regulates diverse biological phenomena on a number of levels. Additionally, RNA contributes to the pathogenesis of a variety of diseases, ranging from human cancers to bacterial and viral infections. However, targeting RNA with small molecules has historically proven challenging. Nonetheless, recent efforts have demonstrated that at least some types of RNA are in fact targetable with drug-like small molecules. This workshop will focus on approaches for targeting RNA with small molecules, including researchers from both academia and industry. Discussions will include the types of RNA that are druggable, strategies for identifying biologically active, RNA-binding small molecules, and the future of RNA as a drug target.

Why Attend?

RNA has emerged as a critical regulator of diverse biological processes, including the pathogenesis of a variety of diseases. However, efforts to drug RNA with small molecules lag far behind those targeting proteins. In this workshop, we will discuss various challenges, successes, and methods for targeting RNA with small molecules, as well as the potential for RNA as a drug target going forward.

Who Should Attend?

Anyone interested in the potential for RNA as a drug target, with a focus on small molecules.

What Will Attendees Learn?

Attendees will get perspectives from both industry and academia on approaches for targeting RNA, including high throughput and design-based methodologies.

Detailed Agenda:

12:00 pm Chairperson’s Opening Remarks

John “Jay” Schneekloth Jr., Ph.D., Investigator, Chemical Biology Laboratory; Head, Chemical Genetics Section, Center for Cancer Research, National Cancer Institute, NIH

12:05 Targeting Structurally and Functionally Diverse RNAs with Drug-Like Small Molecules

John “Jay” Schneekloth Jr., Ph.D., Investigator, Chemical Biology Laboratory; Head, Chemical Genetics Section, Center for Cancer Research, National Cancer Institute, NIH

12:40 The Hepatitis C Virus Internal Ribosome Entry Site as a Target for Viral Translation Inhibitors

Thomas Hermann, Ph.D., Associate Professor, Chemistry and Biochemistry; Co-Director, UCSD Center for Drug Discovery Innovation

The HCV IRES contains an RNA conformational switch which is highly conserved in clinical isolates. Viral translation inhibitors have been discovered which lock conformational states of the IRES switch by binding to a deep pocket in the RNA target. We describe structural analysis, mechanism-of action and structure-activity relationship studies of inhibitors targeting the viral RNA switch.

1:15 Refreshment and Networking Break

1:35 Towards Validating ncRNA as a Small Molecule Drug Target

Graham Smith, Ph.D., Director, Medicinal Chemistry, and Project Team Leader, Merck

The human proteome consists of some 25,000 gene targets from which most current drug discovery efforts are based.  However in recent years it has become clear that the human transcriptome contains a similar number of targets whose RNA does not code for any protein. The role of these transcribed non coding RNA targets is the subject of much active research in the field of epigenetics. They have been shown to be involved in regulating a diverse range of cellular functions. Their genetic linkage to diseases and traits is both numerically and statistically the same as that for the protein coding RNA when using Single Nucleotide Polymorphisms and Genome Wide Association Studies We asked ourselves if we could find small molecule leads which could function through binding to putative ncRNA targets by using an analogous approach to our high throughput small molecule – protein discovery platforms at Merck. We initially identified and prioritized over 100 sequences on which to build our experiment. We designed a pragmatic approach to triage these targets using our ALIS affinity selection HTS platform and parts of our small molecule screening collection.

2:10 Discovery of Small Molecule Rescuers of Survival Motor Neuron-2 (SMN2) for the Treatment of Spinal Muscular Atrophy (SMA)

Atwood Cheung, Ph.D., Investigator III, Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Inc.

SMA is rare autosomal recessive neuromuscular disorder, and is the most common lethal monogenic disease of infants and toddlers. SMA is caused by the loss of the survival motor neuron 1 (SMN1) gene. A compensatory gene called SMN2 encodes a mis-spliced RNA transcript and unstable truncated SMN protein. Using novel screening assays, we identified small molecules that correct the splicing defect in the SMN2 gene through stabilization of the spliceosome/pre-mRNA complex. Optimization led to the orally bioavailable drug NVS-SM1 that increased expression of full length SMN protein in the brain of SMA mice, and extended overall survival. NVS-SM1 is currently being evaluated for efficacy in infant SMA patients.

2:45 Panel Discussion, Final Questions and Wrap-Up

3:00 Close of Workshop

Instructors:

John “Jay” Schneekloth Jr., Ph.D., Investigator, Chemical Biology Laboratory; Head, Chemical Genetics Section, Center for Cancer Research, National Cancer Institute, NIH

Dr. Schneekloth received his undergraduate degree from Dartmouth College in 2001, where he worked with Prof. Gordon Gribble. He then moved to Yale University and obtained a Ph.D. from the chemistry department with Prof. Craig Crews in 2006. As a graduate student he studied natural product total synthesis and chemical biology relating to the ubiquitin-proteasome pathway. He then pursued an NIH postdoctoral fellowship with Prof. Erik Sorensen at Princeton University, where he worked on the development of a new multicomponent reaction and the application of this reaction to the synthesis of analgesic natural products. He returned to Yale in 2009 where he worked as a medicinal chemist at the Yale Small Molecule Discovery Center. In 2011, Dr. Schneekloth joined NCI where his research involves using synthetic chemistry and high throughput chemical biology approaches to develop chemical probes of signal transduction pathways and gene expression. Specific areas of interest include protein sumoylation (including mechanistic probes, natural products, and synthetic inhibitors) and the use of small molecule microarrays to identify RNA- and DNA-binding small molecules.

Thomas Hermann, Ph.D., Associate Professor, Chemistry and Biochemistry; Co-Director, UCSD Center for Drug Discovery Innovation

Thomas Hermann received a Ph.D. from the Ludwig-Maximilians University in Munich, Germany, and after postgraduate work in Strasbourg, France, and at the Sloan-Kettering Cancer Center in New York joined Anadys Pharmaceuticals in San Diego where he participated in the discovery of the HCV drug setrobuvir. In 2005, he joined the Department of Chemistry & Biochemistry at UC San Diego where he also serves as the founding director of the Center for Drug Discovery Innovation. His research interests are focused on RNA as a drug target and RNA nanotechnology.

Graham Smith, Ph.D., Director, Medicinal Chemistry, and Project Team Leader, Merck

Dr. Smith is currently director of Medicinal Chemistry at Merck Research Laboratories in Boston. He is active in the areas of small molecule lead discovery, chemical technologies and medicinal chemistry research. He graduated from the University of Nottingham, UK and continued there to complete a Ph.D. in natural product synthesis with Prof. Gerry Pattenden. He then continued work in the area of natural product research at the Ohio State University under the guidance of Prof. Leo Paquette. Dr. Smith has worked as a medical chemist in the pharmaceutical industry in positions of increasing responsibility for over 20 years for Sanofi, Pfizer and Merck.

Atwood Cheung, Ph.D., Investigator III, Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Inc.

Atwood Cheung is a Research Investigator at Novartis Institutes for BioMedical Research, and received his Ph.D. in Organic Chemistry from Boston College. Over the past 12 year, he has led new target discovery and drug development efforts in oncology, immunology, and neuroscience. He was instrumental in the discovery of tankyrase as a novel target for cancer, and more recently, advancement of a novel RNA splicing modulator into the clinic for Spinal Muscular Atrophy.