Development of bivalent degraders targeting Aurora kinase A for the treatment of polycystic kidney disease (Old ID 31137)
Role
Principal Investigator
Description
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common, potentially fatal, monogenic disease. It is characterised by hyperproliferative formation of fluid-filled cysts from renal epithelia, which progressively ablate healthy renal tissue requiring dialysis or renal transplant to prevent death. It affects 1 in 500-1000 Australians and makes up 5% of end stage renal disease patients. The only approved therapy is a drug called tolvaptan, which inhibits the vasopressin receptor, thereby treating a symptom. Unsurprisingly, tolvaptan has only modest benefits, increasing patient lifespan by ~2.6 years at a cost of US$744K per quality-of-life-year gained. The drug has considerable side effects, including the potential for liver toxicity, with a borderline cost-benefit-risk profile. Consequently, ~24% patients discontinue use. Recently, a Phase II/III trial of Sanofi’s heralded breakthrough therapy, venglustat, was halted due to failure to prevent cyst growth. Rapamycin has also failed in clinical trials previously. As such, any therapeutic treatment that could halt/slow disease progression would be paradigm-shifting to meet this unmet need. We have shown that ADPKD can be halted by genetic ablation of Aurora kinase A (AURKA). Thus, AURKA is a key driver of this disease. We have now developed a small molecule that potently degrades AURKA at low nanomolar levels. This targeted protein degrader (TPD), which we call TPD100, is on the precipice of a significant value inflexion point that will be realized through the combination of its current in vitro cell-based and in vivo potency, combined with a future strong intellectual property position, and evidence of efficacy and safety in ADPKD animal models. This grant will support the development of a novel and patent-protected TPD that is safe and efficacious in ADPKD animal models with once-weekly subcutaneous dosing, representing a very attractive investment package as we progress towards a human ADPKD therapy.
Date
01 Jan 2023 - 31 Dec 2024
Project Type
NON_FUNDED_PROJECT
Keywords
ADPKD;Aurora kinas A
Funding Body
National Health and Medical Research Council (NHMRC)
Amount
0
Project Team
N/A