Journal article
Optimized Synthetic Flavonols Support Senescence Clearance and Lung Fibrosis Resolution
ACS pharmacology & translational science, Vol.8(9), pp.3033-3046
09/12/2025
DOI: 10.1021/acsptsci.5c00231
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease with undefined etiology and minimally effective therapies. The greatest risk factor for developing IPF is aging. The central paradigm to developing antifibrotic drugs for the last half century has focused on directly targeting proliferative lung fibroblasts. However, recent high-resolution analyses of IPF patient lungs suggests disease unique populations of resident lung cells are enriched for markers of senescence. Published work by our group and others further supports that senescent cells are key drivers of fibrosis and may provide an opportunity to develop an effective antifibrotic drug. Multiple naturally derived flavonoids can selectively induce apoptosis in senescent cells (senolytic) and improve end points in models of lung fibrosis; however, these natural phytochemicals are not structurally optimized to maximize their translational potential. Inspired by this opportunity we have performed hit-to-lead studies and medicinal chemistry optimization to generate a novel synthetic flavanoid (F-4N) with similar to 50x greater senolytic potency in vitro- compared to fisetin or quercetin, two naturally derived senolytic flavonols. Furthermore, in bleomycin injury models of lung fibrosis we have shown treatment with F-4N (10 mg/kg-30 mg/kg, daily) promotes reduced senescence burden, resolution of chronic lung fibrosis, and markers of enhanced alveolar epithelial repair.
Details
- Title: Subtitle
- Optimized Synthetic Flavonols Support Senescence Clearance and Lung Fibrosis Resolution
- Creators
- Jeffrey A. Meridew - Mayo ClinicJohn A. Vu - Mayo ClinicDaniela Chow - Mayo ClinicAna Maria Diaz Espinosa - Mayo ClinicNamita Saraf - Mayo ClinicAshley Y. Gao - Mayo ClinicJair Machado Espindola-Netto - Mayo ClinicSara Dresler - Mayo ClinicMadison G. Whaley - Mayo ClinicKyoung M. Choi - Mayo ClinicYong Li - Mayo ClinicHelene Martini - Mayo ClinicEva Carmona Porquera - Mayo ClinicPatrick A. Link - Mayo ClinicThomas M. Kollmeyer - Mayo ClinicJoao F. Passos - Mayo ClinicMarissa J. Schafer - Mayo ClinicNathan K. Lebrasseur - Mayo Clinic in FloridaDaniel J. Tschumperlin - Mayo ClinicAndrew J. Haak - Mayo Clinic
- Resource Type
- Journal article
- Publication Details
- ACS pharmacology & translational science, Vol.8(9), pp.3033-3046
- DOI
- 10.1021/acsptsci.5c00231
- ISSN
- 2575-9108
- eISSN
- 2575-9108
- Publisher
- American Chemical Society
- Number of pages
- 14
- Grant note
- Brewer Family Career Development Award in Support of Idiopathic Pulmonary Fibrosis NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Boehringer Ingelheim Discovery award; Boehringer Ingelheim American Lung Association Dalsemer Mayo Clinic Office of Translation to Practice Accelerator Award Glenn Foundation for Medical Research CDMRP PRMRP HT9425-24-1-0208-01 / Robert and Arlene Kogod Center on Aging Career Development Award 1045091 / DoD; United States Department of Defense T32GM145408 / National Institute on Aging; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA)
- Language
- English
- Date published
- 09/12/2025
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Craniofacial Anomalies Research Center
- Record Identifier
- 9984963154602771
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