While small molecules have long been the cornerstone of the pharmaceutical industry, there is increasingly a demand for innovative precision approaches, often synonymous with biologic therapies. Yet a quiet resurgence in the small molecule sector is building momentum, with its sights set on what was previously considered an “undruggable” target—human RNA.
RNA-based therapeutics have garnered much attention in recent years. Ionis Pharmaceuticals’ antisense oligonucleotide (ASO) therapy Spinraza (nusinersen) was approved for spinal muscular atrophy (SMA) in 2016 and the first RNA interference (RNAi) therapeutic, Alnylam Pharmaceuticals’ Onpattro (patisiran), gained approval in 2018. In addition, the 2024 Nobel Prize in Physiology or Medicine was awarded to the discovery of microRNA (miRNA) and its role in post-transcriptional gene regulation.
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Traditional protein targets are becoming increasingly saturated, says Ken Tajiri, COO of the Kyoto, Japan-headquartered biotech xFOREST Therapeutics, thereby driving interest in alternative approaches. However, RNA-based therapeutics have often been hindered by delivery challenges due to the large, hydrophilic nature of RNA and its susceptibility to degradation. It is argued that RNA-targeted small molecules could offer the same transcription-level intervention, while providing the added benefits of oral availability and scalable manufacturing.
Traditional small molecule drug discovery is predicated on the identification of well-defined binding pockets, which is not conducive to the dynamic nature and relative thermodynamic instability of RNA in comparison with proteins. Nonetheless, advances in the understanding of RNA structural biology and high-throughput screening techniques have allowed for the identification of RNA–small molecule binding interactions. The key challenge has now evolved from identification of RNA binders to enhancing RNA selectivity, says Tajiri.
A succession of partnerships with biotechs focused on RNA-modulating small molecules have signalled big pharma’s growing interest in the space. In 2025 alone, Merck KGaA announced a collaboration with Waltham, Massachusetts-based Skyhawk Therapeutics in a deal worth up to $2bn; Daiichi Sankyo partnered with Seattle, Washington-based Wayfinder Biosciences for use of its drug discovery platform in neurodegenerative disease and Astellas Pharma revealed plans to collaborate with xFOREST to utilise its RNA splicing-targeted drug discovery platform.
Increased traction for RNA-targeting small molecules
Beyond xFOREST’s collaboration with Astellas, the biotech has also partnered with Daiichi Sankyo, Takeda Pharmaceutical, Otsuka Holdings, and several EU-based global pharma companies, says Tajiri. Industry interest has been increasing, particularly from overseas companies, he notes. The collaboration can take two forms, supporting RNA-targeted drug discovery from scratch, or advancing lead compounds derived from xFOREST-identified hit molecules, he adds. Sector progress has been driven, in part, by the landmark success of Roche’s oral SMA drug Evrysdi (risdiplam), he says, which first received FDA approval in 2020. SMA is characterized by deficient SMN protein. Evrysdi binds two sites on exon 7 of the SMN2 pre-mRNA—namely, ESE2 and 5’ss—to promote their inclusion in the mature transcript, thereby increasing functional SMN protein levels.
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By GlobalDataMeanwhile, clinical-stage Watertown, Massachusetts-headquartered Remix Therapeutics collaborated with Johnson & Johnson for exclusive rights to three specific targets in immunology and oncology, for a $45m upfront payment and other payments potentially exceeding $1bn.
Pharma companies are looking for new ways to address an unmet need, says Peter Smith, CEO of Remix. He also reports an uptick in interest in this modality, likely driven by positive data readouts from Remix’s portfolio. In January 2024, Remix formed a partnership with Roche for the discovery and development of small molecule therapeutics modulating RNA processing. The deal included a $30m upfront payment and up to $1.12bn in milestone payments and royalties.
Discovery platforms for RNA-targeted small molecules
The RNA field is powered on computational sciences, says Matthew Disney, PhD, institute professor at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, Florida. AI also has the potential to enhance computational approaches and become increasingly effective as larger high-quality datasets are generated. However, AI is not a fix-all approach and the focus of research should center on how technological advancements can translate into tangible benefits to patients, says Disney. Approximately 1% of human DNA is made into protein, while 80% is converted to RNA and “that’s the tip of the iceberg,” says Disney, highlighting the substantial role of non-coding RNAs in human disease. Tapping into RNA could vastly expand the array of druggable targets, but identifying them is a major hurdle.
Remix aims to circumvent this barrier by incorporating functional screening assays into its drug discovery platform REMaster, says Smith. REMaster utilises machine learning to identify targetable mRNA exon sites within its transcriptome database and assesses their outcome on gene and protein expression via cell-based high-throughput screening. Unique insights into the chemistry required for RNA binding support the development of Remix’s proprietary chemical library—purpose built for compounds that can interact with RNA processing mechanisms, says Smith.
Meanwhile, xFOREST operates two complementary platforms for drug discovery. MatrixFOREST identifies druggable pockets within 3D RNA structures, using both biochemical wet-lab data and analyses based on public databases. The SpliceVerse platform leverages bioinformatics to identify RNA regions that are prone to mis-splicing and therefore amenable to therapeutic modulation. In parallel, the company has built an RNA-focused compound library, exploring regions of chemical space distinct from that of traditional protein-targeted drugs, says Tajiri.
RNA-targeting drugs in the clinic
Remix’s REM-422 is in two Phase I clinical trials studying adenoid cystic carcinoma (NCT06118086) and acute myeloid leukemia/myelodysplastic syndromes (NCT06297941). This drug reduces expression of the oncogenic transcription factor MYB. The development of drugs that directly target transcription factors has been largely unsuccessful, says Smith. REM-422 functions by binding a component of the spliceosome and promoting inclusion of an exon that contains a premature termination codon, thereby promoting degradation of MYB mRNA by nonsense-mediated decay.
Skyhawk’s Huntington disease therapy SKY-0515 is being studied in the Phase II/III FALCON-HD study (NCT06873334), after the therapy demonstrated a mean improvement in Composite Unified Huntington’s Disease Rating Scale (cUHDRS) from baseline in patients with Huntington’s disease in a Phase I trial. The small molecule RNA-splicing modulator SKY-0515 functions by reducing levels of both mutant HTT protein and DNA repair protein PMS1, which drives somatic CAG repeat expansion.
Preclinical research by Disney’s lab helped lay the foundation for drug discovery in RNA repeat expansion diseases such as Huntington’s and amyotrophic lateral sclerosis (ALS). Using advanced computational methods, his group designed a small molecule to selectively bind unique structures formed at specific RNA codon repeats, which was shown to alter local UU internal loop structure thereby limiting protein binding, and subsequently resulting in degradation by the RNA exosome. When toxic RNAs are key drivers of disease, they often harbour unique folds and therefore may be particularly amenable to RNA-targeting drugs, says Disney.
Remaining challenges and future directions
Tajiri and Disney agree that drug selectivity and safety are the biggest barriers to RNA-targeted small molecule drug development. The dynamic properties of RNA increase risk of off-target effects and toxicity, adds Tajiri.
To tackle this challenge, Remix has developed ligand bound crystal and cryo-EM RNA structures, which Smith says offer a “unique lens” into specificity and selectivity of molecules. Meanwhile, xFOREST uses a selectivity profiling approach, whereby the binding strength of the molecule across many RNAs is assessed.
While certain techniques could enhance drug specificity, the scientific complexity and unique chemical characteristic of RNA-binding molecules may deter others from entering the space, says Smith. Nonetheless, he highlights increased awareness and willingness in the field, emphasizing the breadth of opportunity and “space for multiple companies to be very successful.”
