Targeting NF-kB/DNA interaction with GY971: a novel strategy to modulate neutrophil recruitment in cystic fibrosis

Objectives: Despite the transformative impact of Highly Effective CFTR Modulator Therapy (HEMT) on people with Cystic Fibrosis (pwCF), persistent pulmonary inflammation remains a critical driver of progressive lung damage. Current anti-inflammatory options are limited by significant side effects, highlighting an urgent need for safe, HEMT-compatible therapies that specifically target the excessive influx of polymorphonuclear neutrophils (PMNs) into the airways. We characterized GY971, a novel anti-inflammatory candidate designed to reduce PMN recruitment by downregulating chemokine expression in respiratory epithelial cells, without the cyclooxygenase (COX) inhibition associated with traditional NSAIDs. Methods: GY971 was evaluated across several in vitro, ex vivo, and in vivo models, including primary CF bronchial/nasal cells (ALI culture), zebrafish, and murine lung infection models. Results: Our findings demonstrate that GY971: -Inhibits the release of PMN-recruiting chemokines at nanomolar concentrations in primary CF epithelial cells. -Decreases in vivo PMN infiltration in infected models without compromising bacterial clearance. -Maintains full compatibility with HEMT, showing no interference with F508del-CFTR functional rescue. -Exhibits a favorable safety profile, with no detectable toxicity in zebrafish or murine organs, no genotoxicity, and no significant off-target activity on the SafetyScreen44™ panel. Conclusion: The activity of GY971 is mediated by interference with the interaction between activated NF-kB and its consensus DNA sequences within the promoters of key pro-inflammatory cytokines. This mechanism parallels the beneficial effects of high-dose ibuprofen on PMN reduction but avoids the gastrointestinal toxicity linked to COX-1 inhibition. Recognized as an Orphan Drug by the EMA in 2024, GY971 represents a promising, highly specific approach to managing CF airway inflammation.