RNA-Targeting Small Molecules Emerge as New Frontier in Drug Discovery with Major Pharma Partnerships
核心洞察
Remix Therapeutics (搜索) secured major partnerships with Johnson & Johnson ($45M upfront, potential $1B+) and Roche ($30M upfront, $1.12B in milestones) for RNA-targeting small molecule development.
The company's lead candidate REM-422 is advancing through Phase I trials for adenoid cystic carcinoma (搜索) and acute myeloid leukemia (搜索) by targeting the oncogenic transcription factor MYB (搜索).
Skyhawk Therapeutics (搜索)' RNA-splicing modulator SKY-0515 demonstrated clinical improvement in Huntington's disease (搜索) patients and is now in Phase II/III trials.
RNA-targeting small molecules are gaining significant momentum in pharmaceutical development, with clinical-stage companies securing major partnerships and advancing promising candidates through clinical trials. The emerging field represents a paradigm shift in drug discovery, potentially unlocking vast new therapeutic opportunities by targeting RNA processing mechanisms rather than traditional protein targets.
Major Industry Partnerships Drive RNA Drug Development
Watertown, Massachusetts-based Remix Therapeutics (搜索) has established substantial partnerships with pharmaceutical giants, signaling growing industry confidence in RNA-targeting approaches. The company collaborated with Johnson & Johnson for exclusive rights to three specific targets in immunology and oncology, securing a $45 million upfront payment with additional payments potentially exceeding $1 billion.
"Pharma companies are looking for new ways to address an unmet need," says Peter Smith, CEO of Remix Therapeutics (搜索), who reports an uptick in interest in this modality, likely driven by positive data readouts from Remix's portfolio.
In January 2024, Remix formed another significant partnership with Roche for the discovery and development of small molecule therapeutics modulating RNA processing. This deal included a $30 million upfront payment and up to $1.12 billion in milestone payments and royalties.
Computational Platforms Enable RNA Target Discovery
The RNA field is powered by computational sciences, according to Matthew Disney, PhD, institute professor at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology in Jupiter, Florida. Disney emphasizes the vast potential of RNA targeting, noting that approximately 1% of human DNA is made into protein, while 80% is converted to RNA, and "that's the tip of the iceberg," highlighting the substantial role of non-coding RNAs in human disease.
Remix aims to overcome target identification barriers through its drug discovery platform REMaster, which utilizes 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. The platform supports development of Remix's proprietary chemical library, purpose-built for compounds that can interact with RNA processing mechanisms.
Meanwhile, xFOREST (搜索) 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 prone to mis-splicing and therefore amenable to therapeutic modulation.
Clinical Progress in RNA-Targeted Therapeutics
Remix's REM-422 Advances in Oncology
Remix's lead candidate REM-422 is currently in two Phase I clinical trials studying adenoid cystic carcinoma (搜索) (NCT06118086) and acute myeloid leukemia (搜索)/myelodysplastic syndromes (搜索) (NCT06297941). The drug reduces expression of the oncogenic transcription factor MYB (搜索), addressing a historically challenging target class.
"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 (搜索) mRNA by nonsense-mediated decay.
Skyhawk's Huntington's Disease Therapy Shows Promise
Skyhawk Therapeutics (搜索)' Huntington disease therapy SKY-0515 is being studied in the Phase II/III FALCON-HD study (NCT06873334), following positive Phase I results. The therapy demonstrated a mean improvement in Composite Unified Huntington's Disease (搜索) Rating Scale (cUHDRS) from baseline in patients with Huntington's disease.
The small molecule RNA-splicing modulator SKY-0515 functions by reducing levels of both mutant HTT (搜索) protein and DNA repair protein PMS1 (搜索), which drives somatic CAG repeat expansion.
Foundational Research Supports Clinical Development
Preclinical research by Disney's laboratory helped establish the foundation for drug discovery in RNA repeat expansion diseases such as Huntington's and amyotrophic lateral sclerosis (搜索) (ALS). Using advanced computational methods, his group designed a small molecule to selectively bind unique structures formed at specific RNA codon repeats, which altered local UU internal loop structure, limited protein binding, and resulted 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.
Addressing Selectivity and Safety Challenges
Drug selectivity and safety represent the biggest barriers to RNA-targeted small molecule drug development, according to both industry experts. The dynamic properties of RNA increase risk of off-target effects and toxicity.
To address these challenges, 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 (搜索) uses a selectivity profiling approach, assessing the binding strength of molecules across many RNAs.
While the scientific complexity and unique chemical characteristics of RNA-binding molecules may deter some from entering the space, Smith highlights increased awareness and willingness in the field, emphasizing the breadth of opportunity and "space for multiple companies to be very successful."