Tauopathies are neurodegenerative diseases caused by abnormal accumulation of 4R Tau isoforms, often due to MAPT exon 10 splicing mutations. We developed novel splicing modulator compounds (SMCs) that promote exon 10 exclusion. In FTD patient-derived neurons carrying Tau-P301L or S305N mutations, SMCs reduced 4R Tau expression, pTau levels, oligomeric and insoluble Tau species, and rescued Tau-induced toxicity. Importantly, lead SMCs also reduced pTau in the brains of Tau-N279K mutant mice. These results support the therapeutic potential of SMCs as a disease-modifying strategy for 4R tauopathies by directly targeting the transcript to restore proper MAPT splicing and reduce Tau pathology.

Small molecules that modulate mRNA splicing are an ideal modality for treatment of neurodegenerative disorders with high unmet need, due to their brain penetration and oral bioavailability. Here we present an update on our work towards the development of splicing modulators that prevent somatic expansion in Huntington’s Disease. We will discuss the preclinical data on the safety and efficacy of our lead molecule and its progress towards clinical development.

Huntington’s disease (HD) is a dominant neurological disorder caused by an expanded CAG repeat in HTT. Lowering mutant huntingtin has been proposed for treating HD, but genetic modifiers implicate somatic CAG repeat expansion as the driver of onset. We find that branaplam and risdiplam, small-molecule splice modulators that lower HTT, also decrease the rate of CAG repeat instability through pseudoexon inclusion in age-at-onset modifier, PMS1.

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.

Our mission at Arrakis is to solve very broadly the problem of how to drug RNA with small molecules. This presentation will provide an update on the platform we have built to achieve that mission and provide early data on specific mRNA targets.

Familial dysautonomia (FD), or hereditary sensory and autonomic neuropathy type III, is a rare peripheral neuropathy that is caused by a mutation that disrupts ELP1 RNA splicing. We initially discovered that the plant cytokinin kinetin was a potent modulator of ELP1 splicing and have since worked to develop a potent and specific splice modulator compound to treat FD patients. We are currently working with the NINDS Blueprint Neurotherapeutics Network to complete IND-enabling studies.

Proliferating cell nuclear antigen (PCNA) plays an essential role in regulating DNA synthesis and repair and is indispensable to cancer cell growth and survival. It represents an attractive molecular target to develop broad-spectrum anti-cancer agents. By targeting a cancer specific domain of PCNA, we identified a novel compound, AOH1996, which selectively kills cancer cells, but causes no significant toxicity to a broad range of non-malignant cells. AOH1996 is in clinical trials.

Understanding how small molecules act remains a major challenge in drug discovery. Single-molecule tracking enables direct visualization of target dynamics in living cells, extending conventional approaches. Using Werner syndrome helicase (WRN) as a case study, we quantified real-time changes in mobility and chromatin engagement induced by inhibitors, revealing their mode of action. This demonstrates the power of motion-based measurements to uncover mechanisms and accelerate therapeutic discovery.

Nucleic acids (DNA, RNA) adopt a variety of shapes in solution. This continuum of shapes and their recognition by small molecules and proteins play an important role in determining their function. We have incorporated shape-specific principles in our design of nucleic acid binding ligands. This presentation will discuss our approach using peptide-aminosugars in targeting RNA and DNA shapes and structures of relevance in therapeutic applications and fundamental biological processes.

In distinct genetic contexts, including 9p21.3-deleted and high microsatellite instability (MSI-H) tumors, we found that phenotypically destabilized SKI complex leads to dependence on the PELO–HBS1L ribosomal rescue complex. PELO–HBS1L and SKI complex synthetic lethality alters the normal cell cycle and drives the unfolded protein response through the activation of IRE1, as well as robust tumor growth inhibition. Our results indicate that PELO and HBS1L represent novel therapeutic targets whose dependence converges upon SKI complex destabilization, a common phenotypic biomarker in diverse genetic contexts representing a significant population of patients with cancer.

Our study identifies and validates synthetic lethal (SL) interactions in colorectal cancer (CRC), focusing on actionable vulnerabilities linked to APC and KRAS mutations. By integrating engineered primary cancer models, patient-derived xenografts, and transcriptomic profiling, we discovered novel SL targets that offer a promise for personalized CRC therapies. These findings bridge preclinical and clinical research, paving the way for safer and more effective treatment options tailored to CRC's unique mutational landscape.

Small-molecule targeting of RNAs has become a leading drug discovery approach. However, identifying RNA binders that produce functional effects remains a significant challenge. Endogenous cellular metabolites provide an untapped source of inspiration for small-molecule leads. Atavistik Bio has leveraged the AMPS (Atavistik Metabolite Proprietary Screening) platform to screen metabolites against RNA. We will present the AMPS platform, our hit identification workflows, and a case study of the SERPINA1 5’UTR.