Weill Cornell Medicine has received a USD 4.2 million National Institute on Aging (NIA) RF1 grant to advance preclinical development of small molecules that selectively suppress mitochondrial reactive oxygen species (ROS) production as a potential disease-modifying therapy for Alzheimer's disease (AD) and related dementias.
The award funds work led by principal investigator Adam L. Orr on suppressors of electron leak (SELs), specifically a subclass called S3QELs ("sequels") that selectively inhibit ROS generation at mitochondrial respiratory complex III. The compounds are reported to be orally bioavailable, blood-brain barrier-penetrant, and well-tolerated in animal models over extended treatment periods, with preclinical evidence of reduced neuroinflammation and neurodegeneration in proteinopathy models.
The scientific premise distinguishes mitochondria-derived ROS as an upstream driver of neuropathogenic cascades implicated across multiple dementia subtypes — including amyloid pathology, tauopathy, and apolipoprotein E4 (ApoE4)-linked neurodegeneration — rather than targeting a single proteinopathy. The research team said first-generation S3QELs showed suboptimal drug-like properties, and the grant will fund a medicinal chemistry campaign to identify optimized second-generation analogs, combining structure-guided design, pharmacokinetic and pharmacodynamic profiling, and proteomic and transcriptomic characterization in human neural cells and preclinical dementia models.