RNA-Modulating Small Molecule Drugs

Novel Approaches to Target RNA Structure, Binding, Interactions, and Function

April 14, 2025 ALL TIMES PDT

With an increased understanding of RNA structure, function, and interactions, there is greater interest in finding small molecules to target RNA for therapeutic intervention, as they offer enhanced stability, oral bioavailability, and better drug-like properties. However, identifying the right disease-causing RNA and evaluating the downstream physiological responses after small molecule binding can be quite challenging. Challenges also exist in terms of optimizing the specificity, selectivity, and safety of these small molecules in vivo. Cambridge Healthtech Institute’s symposium on RNA-Modulating Small Molecule Drugs will highlight some of the innovative approaches and technologies being used.

Monday, April 14

12:00 pmPre-Conference Symposium Registration

1:00 pmWelcome Remarks

1:10 pm

Chairperson's Remarks

Thomas Hermann, PhD, Professor, Department of Chemistry & Biochemistry, University of California, San Diego

1:15 pm

Discovery of Condensate-Modulating Covalent Small Molecules

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

We present the use of SuTEx to disrupt cytoplasmic condensates by covalently binding tyrosine residues, enabling pharmacological intervention in ribonucleoprotein (RNP) functions within cancer cells. We deployed a chemoproteomics platform using SuTEx chemistry for chemical biology exploration of P-bodies and SGs. Key findings include: (i) the development of a SuTEx-enabled screening platform to target ligandable tyrosine (Y) and lysine (K) residues in stressed cancer cells, (ii) the identification of SuTEx ligands that can either disrupt or prolong the formation of SGs and P-bodies in stressed cells, (iii) the discovery of SuTEx ligands targeting EDC3 Y475 site and G3BP1 Y40.

1:45 pm

Visual Biology Drug Discovery

Generoso Ianniciello, Chief Business Officer, Anima Biotech

Lightning.AI, Anima’s groundbreaking TechBio platform, uses Visual Biology to transform target and drug discovery. With PathwayLight, it generates deep, large-scale disease biology data by imaging cellular pathways in healthy and diseased cells. This data trains neural networks to identify “disease signatures,” uncover novel targets, and discover small molecules that modulate mRNA biology. Validated through partnerships with Lilly, Takeda, and AbbVie, Lightning.AI now powers over 20 drug discovery programs.

2:15 pm

An Integrative Structure-Based Approach to Discovering mRNA-Targeted Small Molecules

Elena Menichelli, PhD, Director & Head, Structural Biology, Arrakis Therapeutics

Using orally bioavailable small molecules to modulate the function of messenger RNAs offers a promising strategy for developing new therapies that extend beyond currently druggable protein targets. Here, we discuss our structure-based approach to discovering mRNA-targeted small molecules, touching on unique challenges in building a broad and robust platform.

2:45 pm

Mirror-Image RNA-Targeted DEL Screens

Zhen Chen, Senior Principal Research Scientist, Lead Discovery & Biochemistry, X-Chem, Inc.

We present mirror-image RNA-targeted DNA-encoded library (DEL) screening as a novel approach to discover small molecule ligands for RNA. Our strategy eliminates false enrichment from DNA:RNA hybridization, enhances the enrichment of genuine target engagers, and enabled the discovery of novel, specific binders to expansion repeat, splice site, and riboswitch targets. Our method unleashes the unparalleled throughput of DEL for RNA-targeted drug discovery.

3:15 pmNetworking Refreshment Break

3:30 pm

Enhancing Activation of a Novel Splice Site Sequence: Development of a Small Molecule Splicing Modifier Therapy for Genetic Diseases

Jigar Patel, PhD, Associate Director, Medicinal Chemistry, PTC Therapeutics

The viability of an emerging small molecule splicing program often depends on the ability to drive potency towards a particular target, while maintaining reasonable selectivity. This presentation highlights our hit-to-lead efforts towards the development of a splicing modifier of an undisclosed gene of high interest.

4:00 pm

Recent Advances Developing RNA Splicing Modulators to Treat Incurable Diseases

Diane Hamann, PhD, Principal Scientist, Medicinal Chemistry, Rgenta Therapeutics

Rgenta Therapeutics has developed a proprietary, integrative RNA-targeting oral small molecule discovery platform to deliver first-in-class therapies. We are pursuing targets in the oncology and neurological diseases space, exemplified by the oncogenic transcription factor c-MYB and the PMS1 gene. In this presentation, we’ll share an overview of our platform and recent progress on selected targets.

4:30 pm

Identification of Functional Small Molecule Binders of UTRs in mRNAs Relevant to Human Disease

Thomas Roddy, PhD, Senior Vice President, Platform Technology, Atavistik Bio

Metabolite binding to RNA can modulate gene expression. We have developed a technology using LC/MS-based metabolomics and an endogenous metabolite library to systematically discover functional binding pockets on RNA. These pockets enable an efficient drug discovery campaign using AI/ML-enabled structure-based drug design. This process has been successfully executed on several RNA targets in multiple therapeutic areas. Our discovery of compounds that bind to the UTR of human SERPINA1, which is implicated in Alpha-1-Antitrypsin (A1AT) deficiency, will be presented.

5:15 pmClose of Symposium

5:30 pmDinner Short Course Registration

6:00 pmDinner Short Courses*

*Premium Pricing or separate registration required. See Short Courses page for details.