Development of potent, selective cPLA2 inhibitors for targeting neuroinflammation in Alzheimer's disease and other neurodegenerative disorders

Anastasiia V Sadybekov; Marlon Vincent Duro; Shaowei Wang; Brandon Ebright; Dante Dikeman; Cristelle Hugo; Bilal Ersen Kerman; Qiu-Lan Ma; Antonina L Nazarova; Arman A Sadybekov; Isaac Asante; Stan G Louie; Vsevolod Katritch; Hussein N Yassine

doi:10.1038/s44386-025-00035-0

Development of potent, selective cPLA₂ inhibitors for targeting neuroinflammation in Alzheimer's disease and other neurodegenerative disorders

NPJ Drug Discov. 2026;3(1):2. doi: 10.1038/s44386-025-00035-0. Epub 2026 Jan 7.

Authors

Anastasiia V Sadybekov^#^{1

2}, Marlon Vincent Duro^#³, Shaowei Wang^#⁴, Brandon Ebright⁵, Dante Dikeman⁵, Cristelle Hugo⁴, Bilal Ersen Kerman⁴, Qiu-Lan Ma⁴, Antonina L Nazarova^{1

2}, Arman A Sadybekov¹, Isaac Asante⁶, Stan G Louie^{5

7}, Vsevolod Katritch^{1

2

8}, Hussein N Yassine^{4

9}

Affiliations

¹ Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA USA.
² Center for New Technologies in Drug Discovery and Development, Bridge Institute, Michelson, Los Angeles, CA USA.
³ Department of Radiology, Keck School of Medicine, Los Angeles, CA USA.
⁴ Department of Neurology, Keck School of Medicine, Los Angeles, CA USA.
⁵ Department of Clinical Pharmacy, Mann School of Pharmacy, Los Angeles, CA USA.
⁶ Department of Ophthalmology, Keck School of Medicine, Angeles, CA USA.
⁷ Department of Pharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, Los Angeles, CA USA.
⁸ Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA USA.
⁹ Center for Personalized Brain Health, University of Southern California, Los Angeles, CA USA.

^# Contributed equally.

Abstract

Chronic neuroinflammation plays a key role in the progression of Alzheimer's disease (AD), and the cytosolic calcium-dependent phospholipase A₂ (cPLA₂) enzyme is a critical mediator of inflammatory lipid signaling pathways. Here we investigate the therapeutic potential of novel cPLA₂ inhibitors in modulating neuroinflammation in AD. By leveraging the giga-scale V-SYNTHES2 virtual screening in on-demand chemical space and conducting two rounds of optimization for potency and selectivity, we have identified BRI-50460, achieving an IC₅₀ of 0.88 nM in cellular assays that measure cPLA₂-mediated arachidonic acid release. In vivo studies revealed favorable brain-to-plasma ratios, highlighting the ability of BRI-50460 to penetrate the central nervous system, modulating neuroinflammatory pathways, and restoring lipid homeostasis. In astrocytes and neurons derived from human induced pluripotent stem cells, BRI-50460 mitigates the effects of amyloid beta 42 oligomers on cPLA₂ activation, tau hyperphosphorylation, and synaptic loss. Our results support that small molecule inhibitors of cPLA₂ can modulate the downstream inflammatory signaling, offering a promising therapeutic strategy for neurodegenerative diseases.

Keywords: Drug discovery; Virtual screening.