Small Molecule Inhibitors of Pathological Stress Granule Formation
This technology is a class of small molecule compounds that block TIA1-driven stress granule formation and the pathological protein aggregation underlying neurodegenerative diseases such as ALS, frontotemporal dementia, and Alzheimer’s disease.
Unmet Need: Disease-modifying therapies that target protein aggregation in neurodegeneration
Neurodegenerative diseases such as ALS, frontotemporal dementia, and Alzheimer’s disease remain without treatments that meaningfully slow their progression. Approved drugs, including riluzole and edaravone for ALS and cholinesterase inhibitors and anti-amyloid antibodies for Alzheimer’s, address symptoms or a single downstream target rather than the protein aggregation and RNA dysregulation that drive these disorders. Efforts to modulate this pathology by inhibiting upstream kinases reduce stress granule formation but lack specificity and carry significant toxicity. No available therapy directly targets the stress granule nucleators responsible for pathological protein aggregation.
The Technology: Small molecules that specifically block TIA1-dependent stress granule assembly
These compounds inhibit the self-multimerization of TIA1, a prion-related RNA-binding protein that nucleates stress granules during cellular stress. By preventing TIA1 multimerization, the compounds block stress granule assembly and stop the recruitment of aggregation-prone proteins implicated in neurodegenerative diseases into these structures. In some cases, these compounds can also accelerate the disassembly of aggregates that have already formed. Initially identified through a high-throughput screen, the series has been extended through the synthesis of novel chemical analogs with improved structure-activity profiles.
The compounds have been validated in human and mouse cell lines and in human motor neurons.
Applications:
- Small-molecule therapeutics for ALS, frontotemporal dementia, and tauopathies including Alzheimer’s disease
- Treatment of Welander distal myopathy and other TIA1-related disorders
- Adjuvant to chemotherapy in cancers that use stress granules to evade cytotoxic drugs, such as KRAS-mutant tumors
- High-throughput screening assay to identify additional stress granule inhibitors
- Research tool for studying stress granule biology, phase separation, and RNA-binding protein dynamics
Advantages:
- Directly targets TIA1, a proximal driver of stress granule formation
- Offers greater specificity than upstream kinase inhibitors
- Shows minimal toxicity and off-target effects
- Both prevents new stress granule assembly and disassembles pre-formed pathological aggregates
- Targets a mechanism of action distinct from marketed neurodegeneration drugs
Lead Inventor:
Patent Information:
Patent Pending
Related Publications:
Tech Ventures Reference:
IR CU16219, CU26002
Licensing Contact: Jerry Kokoshka