![\"\"](\"http:\/\/sites.unica.it\/pe2026\/files\/2026\/05\/Fabiana_Lo_Mascolo-1024x964.jpeg\")
<\/figure>OC17 – Fabiana Lo Mascolo<\/strong><\/p>\n\n\n\n Department of Sciences and Chemical Biology and Pharmaceutical Technology (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy;<\/p>\n\n\n\n e-mail<\/a> – LinkedIn<\/a><\/strong><\/p>\n<\/div><\/div>\n\n\n\n <\/p>\n","protected":false},"excerpt":{"rendered":" OC17 – Fabiana Lo Mascolo Department of Sciences and Chemical Biology and Pharmaceutical Technology (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy; e-mail – LinkedIn Prodrug strategies to improve the drug-like properties of fragment-derived […]<\/p>\n","protected":false},"author":9643,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[1],"tags":[],"class_list":["post-1730","post","type-post","status-publish","format-standard","hentry","category-senza-categoria"],"_links":{"self":[{"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/posts\/1730","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/users\/9643"}],"replies":[{"embeddable":true,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/comments?post=1730"}],"version-history":[{"count":2,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/posts\/1730\/revisions"}],"predecessor-version":[{"id":1801,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/posts\/1730\/revisions\/1801"}],"wp:attachment":[{"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/media?parent=1730"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/categories?post=1730"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/tags?post=1730"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}Prodrug strategies to improve the drug-like properties of fragment-derived Keap1-Nrf2 Inhibitors<\/strong><\/strong><\/td><\/tr> Fabiana Lo Mascolo1<\/sup>,<\/em> Paola Barraja1<\/sup>, Anders Bach2<\/sup>
<\/em>
1<\/em><\/sup> Department of Sciences and Chemical Biology and Pharmaceutical Technology (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy;
2<\/em><\/sup> Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark;<\/td><\/tr>Abstract<\/strong>
Oxidative stress is a key driver of neurodegenerative, inflammatory and renal diseases [1]. Pharmacological activation of the Nrf2 pathway via disruption of the Keap1-Nrf2 protein-protein interaction is a promising therapeutic strategy; however, most non-covalent Keap1 inhibitors rely on carboxylic acid moieties required for binding to the arginine-rich pocket, often resulting in poor membrane permeability and suboptimal drug-like properties [2,3]. To overcome this limitation, we investigated a prodrug approach to transiently mask the carboxylic acid functionality of fragment-derived Keap1 inhibitors identified through fragment-based drug discovery. A focused library of 26 prodrugs was synthesized and evaluated for aqueous solubility (PBS, pH 7.4, 0.5-4% DMSO; 30-200 \u00b5M) and passive permeability using PAMPA. Quantitative LC-MS methods based on selective ion monitoring (SIM) were developed for sensitive compound detection. Initial screening identified three methyl ester derivatives with markedly improved permeability, reaching Pe (cm\/s) values up to 1.16 \u00d710\u207b\u2075 cm\/s versus \u2264 8.62 \u00d710\u207b\u2077 cm\/s for parent acids (~13-fold increase), including complete rescue from undetectable to high permeability. Building on these results, corresponding thiazolidinone-based prodrugs were designed and synthesized to further optimize physicochemical properties and enable ROS-responsive activation. These analogues retained favorable solubility and permeability profiles and were subjected to oxidative activation studies. LC-MS kinetic analysis confirmed concentration-dependent oxidative cleavage. Under mild oxidative conditions (1 mM H\u2082O\u2082), prodrugs showed gradual and controlled degradation, with 56-68% remaining after 180 min, whereas faster conversion occurred at higher ROS levels, indicating a tunable balance between stability and activation. Overall, this study demonstrates that prodrug strategies can effectively address permeability limitations of fragment-derived Keap1 inhibitors while enabling ROS-triggered activation. Selected compounds are currently under biological evaluation in cellular models of Nrf2 activation in collaboration with Prof. Olagnier\u2019s laboratory (Aarhus University). Supporting further development of drug-like modulators of the Keap1-Nrf2 pathway.<\/td><\/tr>References <\/strong>
[1] Cuadrado, A.; Rojo, A.I.; Wells, G.; Hayes, J.D.; Cousin, S.P.; Rumsey, W.L.; Attucks, O.C.; Franklin, S.; Levonen, A.L.; Kensler, T.W.; Dinkova-Kostova, A.T. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat. Rev. Drug Discov. 2019, 18, 295\u2013317. DOI: 10.1038\/s41573-018-0008-x.
[2] Barreca, M.; Qin, Y.; Cadot, M.E.H.; Barraja, P.; Bach, A. Advances in developing noncovalent small molecules targeting Keap1. Drug Discov. Today 2023, 28, 103800. DOI: 10.1016\/j.drudis.2023.103800.
[3] Pallesen, J.S.; Tran, K.T.; Bach, A. Non-covalent Small-Molecule Kelch-like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 (Keap1-Nrf2) Inhibitors and Their Potential for Targeting Central Nervous System Diseases. J. Med. Chem. 2018, 61, 8088\u20138103. DOI: 10.1021\/acs.jmedchem.8b00358.<\/td><\/tr><\/tbody><\/table><\/div><\/figure>\n\n\n\n