
Cambridge Healthtech Instituteの第4回年次会議
RNA-Targeting Small Molecule Drugs
(RNA標的の低分子医薬品)
RNAの構造、結合、相互作用、機能を調節する新規戦略
2023年4月11 - 12日
多様なRNA部分、その構造、機能、相互作用に関する理解が深まるにつれて、科学者はRNAを標的とする低分子の探索を開始しました。低分子は安定性、経口バイオアベイラビリティ、薬物様特性が優れているからです。しかし、疾患の原因となる適切なRNAを特定し、それを調節する低分子を見つけて、下流の生理学的反応を評価することは困難な場合があります。これらのRNAを標的とする低分子のin vivoでの特異性、選択性、安全性を最適化するという点でも、課題が存在します。この「RNA標的の低分子医薬品」に関する会議では、使用されている革新的なアプローチや技術の一部に焦点を当てます。
4月11日(火)
Registration and Morning Coffee7:00 am
Welcome Remarks8:00 am
DEVELOPING RNA MODULATORS
RNAモジュレーターの開発
Discovery of Small Molecule mRNA Modulators Using Phenotypic Screening with AI-Driven MoA Elucidation
Iris Alroy, PhD, Co-Founder & CSO, Anima Biotech
Anima’s mRNA Lightning platform has generated many novel chemical entities that modulate mRNA translation, further contributing to the expanse of the RNA-targeting small molecule field. Anima's phenotypic screening approach systematically evaluates the impact of small molecules on mRNA translation into proteins. Combined with AI-driven MOA elucidation, Anima has identified and validated compounds that are binding to proteins which regulate mRNA translation, offering an opportunity for both tissue-selective and target-specific modulation. Anima’s lead programs in fibrosis and oncology have demonstrated efficacy in animal and patient-derived models and are advancing toward preclinical development.
Pharmacokinetics, Pharmacodynamics, Pharmaceutical Properties, and Efficacy of Small Molecule Splicing Modifiers
Marla Weetall, PhD, Vice President, Pharmacology and Biomarkers, PTC Therapeutics
Utilizing small molecules to modulate splicing has emerged as a successful therapeutic approach to regulating protein expression. Here, three diseases where small molecule splicing modulators can be utilized are described: spinal muscular atrophy, familial dysautonomia, and Huntington’s disease. For each of these indications, I will discuss the correlation between pharmaceutical properties and pharmacokinetics, pharmacokinetics and pharmacodynamics, and the correlation between pharmacodynamics and efficacy.
Small Molecule Splicing Modulators Targeting Huntington's Disease

Zhifeng Yu, PhD, Director, WuXi Biology, WuXi AppTec
New “DNA-Zipper” DEL technology significantly reduces interference between DNA tags and RNA molecules, addressing a key hurdle in screening scalability when targeting RNA with small molecules. With advances in complementary techniques such as ASMS, fragment screening, and SHAPE-MaP to verify RNA quality and characterize RNA-small molecule interactions, RNA-as-a-target now holds the promise of dramatically increasing the pool of druggable targets.
Sponsored Presentation (Opportunity Available)9:55 am
Networking Coffee Break10:10 am
Discovery of Small Molecule RNA Binders That Selectively Stimulate Target RNA Degradation
Peng Yue, PhD, CoFounder & CEO, ReviR Therapeutics, ReviR Therapeutics
Antisense oligonucleotides (ASOs) have demonstrated the ability to functionally reduce the expression of cognate RNAs in cells. However, the therapeutic utility of these molecules has been limited by their tissue distribution and mode of administration. Small molecules present a superior modality that can broadly target tissues and cross the blood brain barrier by oral administration. In this presentation, we will discuss our efforts to selectively target undruggable RNAs with small molecules that induce RNA degradation at meaningful therapeutic concentrations. This presentation will explore the molecular basis for these interactions and examine the functional consequences of target suppression in cellular models of disease.
Discovery of RNA-Targeted Small Molecule Therapeutics
Kathleen McGinness, PhD, Head of Platform Biology, Arrakis Therapeutics
RNA offers a broad array of folded, three-dimensional structures that mediate their functional roles. Our drug discovery platform at Arrakis Therapeutics is directed at the intervention of those functions to therapeutic benefit using drug-like small molecules that bind folded RNA structures. This presentation will touch on some of the unique challenges in building a broad and robust RNA-targeted small molecule platform and provide early data on specific RNA targets.
PANEL DISCUSSION: Challenges with Translating RNA-Targeting Small Molecules into Drugs
Thomas Hermann, PhD, Professor, Department of Chemistry & Biochemistry, University of California, San Diego
Marla Weetall, PhD, Vice President, Pharmacology and Biomarkers, PTC Therapeutics
- Direct-acting small molecule ligands vs. bispecific ligands (degraders, molecular glues)
- Target-directed vs. phenotypic approaches for targeting RNA
- Challenges arising from understanding of RNA biology
- Insights into targeting non-coding RNA
Transition to Lunch12:05 pm
Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own12:15 pm
Session Break12:45 pm
AI FOR TARGETING RNA
RNA標的向けAI
Discovery of Novel Degraders of RNA-Binding Proteins by Integrating Molecular Dynamics with Fragment Screening
Bryce Allen, PhD, Co-Founder & CEO, Differentiated Therapeutics
RNA-binding proteins (RBPs) are paramount effectors of gene expression, and their malfunction underlies the origin of many diseases. However, therapeutically targeting RBPs with small molecules has proven challenging due to highly polar orthosteric ribonucleic interactions and a lack of lipophilic cavities indicative of druggability. We present an integrated screening campaign integrating fragment-based differentiable design with molecular dynamics to discover a cryptic site enabling the discovery of a novel non-functional RBP binder. We demonstrate the physics-driven optimization of this hit molecule to induce the proximity of an E3 ligase, facilitating the proteosome-specific degradation of an RBP and restoring a tumor-suppressive miRNA.
Application of Artificial Intelligence to Discover RNA-Targeting Small Molecules
Sridhar Narayan, PhD, Vice President, ReviR Therapeutics
High-throughput screening of RNA-targeting small molecules remains a challenge due to the lack of RNA-focused small molecule libraries. We applied AI-assisted technology to select a suitable small molecule library and carried out compound screening using ALIS. The increased hit rate was significantly higher compared to our previous campaigns, which demonstrates that AI-driven compound selection strategies can accelerate RNA-targeted small molecule drug discovery.
Unlocking the Druggable Universe of 3D RNA Structures with Artificial Intelligence
Raphael Townshend, PhD, Founder & CEO, 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.
Refreshment Break in the Exhibit Hall with Poster Viewing3:20 pm
PLENARY KEYNOTE SESSION
基調講演(プレナリーセッション)
Plenary Keynote Introduction (Sponsorship Opportunity Available)4:35 pm
Targeting Nodes and Edges in Protein Networks
Michelle Arkin, PhD, Chair and Distinguished Professor, Pharmaceutical Chemistry & Director, Small Molecule Discovery Center, University of California, San Francisco
Protein interaction networks consist of protein nodes and interaction edges. We aim to inhibit or stabilize specific protein-protein interactions to dissect these complex networks for chemical biology and therapeutics discovery. Through covalent fragment-based approaches, we discovered compounds that selectively stabilized the chaperone 14-3-3 bound to diverse client proteins and altered their function. Additionally, function-selective inhibitors for the multifunctional enzyme VCP/p97 are providing new tools and drug leads for cancer.
Welcome Reception in the Exhibit Hall with Poster Viewing5:30 pm
Close of Day6:30 pm
4月12日(水)
Registration Open7:00 am
In-Person Group Discussions with Continental Breakfast7:45 am
Novel Tools and Strategies for Discovery of Small Molecules Targeting RNA
Thomas Hermann, PhD, Professor, Department of Chemistry & Biochemistry, University of California, San Diego
Ken Hsu, PhD, Stephen F. and Fay Evans Martin Endowed Associate Professor, Department of Chemistry, The University of Texas at Austin
Anthony Mustoe, PhD, Assistant Professor, Department of Biochemistry and Molecular Biology, Baylor College of Medicine
- Emerging techniques to study RNA structure and function
- Chemoproteomic methods for systematic profiling of RNA-protein interactions
- Assays to determine if RNA binding/modulation leads to biological consequences
- Challenges and opportunities for developing small molecules targeting RNA
- Developing novel business models in a non-competitive space to accelerate the field
PROBING RNA INTERACTIONS
RNA相互作用のプロービング
Chemical Methods for Investigating the RNA Interactome
Ken Hsu, PhD, Stephen F. and Fay Evans Martin Endowed Associate Professor, Department of Chemistry, The University of Texas at Austin
We present an approach that utilizes 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 domains and discovery of RNA binding activity on proteins without prior RBP annotation. In summary, we present a chemoproteomic method for global quantification of protein-RNA binding activity in living cells.
Remodeling Oncogenic Transcriptomes by Small Molecules Targeting the RNA-binding Protein NONO
Stefan Kathman, PhD, Scientist, Early Discovery, Vividion Therapeutics
We have discovered compounds that covalently engage the RNA-binding protein NONO. These NONO ligands suppress mRNA of several cancer-relevant genes and impair cancer cell proliferation. Surprisingly, these effects were not observed in cells genetically disrupted for NONO, which were instead resistant to NONO ligands. The ligands promote NONO accumulation in nuclear foci and stabilize NONO-RNA interactions, supporting a trapping mechanism that prevents compensatory action of paralog proteins PSPC1 and SFPQ.
Coffee Break in the Exhibit Hall with Poster Awards Announced9:35 am
Poster Award (Sponsorship Opportunity Available)
Targeting RNA with Small Molecules: Tools and Technologies for Medicinal Chemistry
Jay Schneekloth Jr., PhD, Principal Investigator, Chemical Biology Laboratory, NIH NCI
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.
Small Molecules Affecting RNA Function: Target Validation and Functional Binding Assays
Thomas Hermann, PhD, Professor, Department of Chemistry & Biochemistry, University of California, San Diego
Targeting of RNA by small molecule drugs requires modification of RNA target function or stability induced by ligand binding. Surrogate approaches that assess target performance upon structure modification in the context of biological function, and screening assays that couple ligand binding and structure modification are powerful tools to assess feasibility of small molecule targeting for structured RNA domains. I will discuss examples from targeting structured domains in human mRNA and viruses including HCV, Zika virus, and SARS CoV-2.
Discovering and Targeting Functional RNA Structures
Anthony Mustoe, PhD, Assistant Professor, Department of Biochemistry and Molecular Biology, Baylor College of Medicine
RNA structures play essential roles in directing RNA function and are key therapeutic targets. I will discuss our ongoing efforts to develop single-molecule chemical probing technologies to measure complex RNA and RNA-protein structures at high-resolution in living cells. I will further describe new RNA structural mechanisms revealed by these technologies, and our preliminary efforts to target RNA structures to control gene expression.
Close of RNA-Targeting Small Molecule Drugs Conference12:00 pm
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