{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T09:35:25Z","timestamp":1773394525346,"version":"3.50.1"},"reference-count":110,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T00:00:00Z","timestamp":1773360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    Phosphoinositide 3-kinases (PI3Ks) are ubiquitous enzymes, that regulate different cellular functions, most involved in pathogenesis and progression of several oncological diseases. Indeed, some PI3K inhibitors have been approved for blood cancers, such as lymphoma. Interestingly, leniolisib, a selective PI3K\u03b4 kinase inhibitor, has been approved for the rare disease Activated Phosphoinositide 3-kinase Delta Syndrome (APDS). Activation of PI3K\/AKT signaling is downstream to VEGF-A pro-angiogenic signaling, detrimental in diabetic retinopathy progression, a microvascular complication of diabetes mellitus. Recently, a report evidenced that inhibition of class IA PI3K (PI3K\u03b4) delivered beneficial effects in an\n                    <jats:italic>in-vivo<\/jats:italic>\n                    model of diabetic retinopathy. We hereby explored the implication of PI3K signaling in diabetic retinopathy. Moreover, we reviewed the current literature to highlight molecular features of class I PI3K selective inhibitors, to further guide the design of novel selective and safe drugs targeting PI3K\u03b4, for management of diabetic retinopathy or other retinal proliferative diseases.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1744181","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T08:37:35Z","timestamp":1773391055000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Selective phosphoinositide 3-kinase inhibitors and implication in diabetic retinopathy as pharmacological tools"],"prefix":"10.3389","volume":"17","author":[{"given":"Carmela","family":"Bonaccorso","sequence":"first","affiliation":[{"name":"Department of Chemical Sciences, University of Catania","place":["Catania, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Lazzara","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania","place":["Catania, Italy"]},{"name":"Center for Research in Ocular Pharmacology-CERFO, University of Catania","place":["Catania, Italy"]},{"name":"Department of Medicine and Surgery, \u201cKore\u201d University of Enna","place":["Enna, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabel","family":"La Rosa","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania","place":["Catania, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Munzone","sequence":"additional","affiliation":[{"name":"Department of Chemical Sciences, University of Catania","place":["Catania, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandro","family":"Grasso","sequence":"additional","affiliation":[{"name":"Department of Chemical Sciences, University of Catania","place":["Catania, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara B. M.","family":"Platania","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania","place":["Catania, Italy"]},{"name":"Center for Research in Ocular Pharmacology-CERFO, University of Catania","place":["Catania, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudio","family":"Bucolo","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania","place":["Catania, Italy"]},{"name":"Center for Research in Ocular Pharmacology-CERFO, University of Catania","place":["Catania, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"588","DOI":"10.2174\/1573406415666190222125333","article-title":"Discovery of new phosphoinositide 3-kinase Delta (PI3K\u03b4) inhibitors via virtual screening using crystallography-derived pharmacophore modelling and QSAR analysis","volume":"15","author":"Al-Sha\u2019er","year":"2019","journal-title":"Med. Chem. (Los Angeles)"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1007\/s00044-023-03057-3","article-title":"Development of phosphoinositide 3-kinase delta (PI3K\u03b4) inhibitors as potential anticancer agents through the generation of ligand-based pharmacophores and biological screening","volume":"32","author":"Al-Sha\u2019er","year":"2023","journal-title":"Med. Chem. Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"001","DOI":"10.7324\/JAPS.2018.8501","article-title":"QSAR, molecular docking and dynamics studies of quinazoline derivatives as inhibitor of phosphatidylinositol 3-Kinase","volume":"8","author":"Arba","year":"2018","journal-title":"J. Appl. Pharm. Sci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1021\/jm501629p","article-title":"Discovery of (R)-8-(1-(3,5-difluorophenylamino)ethyl)- N, N -dimethyl-2-morpholino-4-oxo-4 H -chromene-6-carboxamide (AZD8186): a potent and selective inhibitor of PI3K\u03b2 and PI3K\u03b4 for the treatment of PTEN-deficient cancers","volume":"58","author":"Barlaam","year":"2015","journal-title":"J. Med. Chem."},{"key":"B5","doi-asserted-by":"publisher","first-page":"D1083","DOI":"10.1093\/NAR\/GKT1031","article-title":"The ChEMBL bioactivity database: an update","volume":"42","author":"Bento","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"B6","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1007\/s00044-012-0081-3","article-title":"QSAR and pharmacophore modeling of N-acetyl-2-aminobenzothiazole class of phosphoinositide-3-kinase-\u03b1 inhibitors","volume":"22","author":"Bharate","year":"2013","journal-title":"Med. Chem. Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"9558","DOI":"10.3390\/IJMS21249558","article-title":"TGF-\u03b2 Serum levels in diabetic retinopathy patients and the role of Anti-VEGF therapy","volume":"21","author":"Bonfiglio","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1586\/EEM.09.19","article-title":"PI3K signaling: a crossroads of metabolic regulation","volume":"4","author":"Braccini","year":"2009","journal-title":"Expert Rev. Endocrinol. Metab."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1596","DOI":"10.1128\/MCB.25.5.1596-1607.2005","article-title":"Phosphoinositide 3-Kinase catalytic subunit deletion and regulatory subunit deletion have opposite effects on insulin sensitivity in mice","volume":"25","author":"Brachmann","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"188","DOI":"10.3389\/FPHAR.2012.00188","article-title":"Ocular drug delivery: a clue from nanotechnology","volume":"3","author":"Bucolo","year":"2012","journal-title":"Front. Pharmacol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/J.JPHS.2018.11.001","article-title":"Long-term efficacy and safety profile of multiple injections of intravitreal dexamethasone implant to manage diabetic macular edema: a systematic review of real-world studies","volume":"138","author":"Bucolo","year":"2018","journal-title":"J. Pharmacol. Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1104","DOI":"10.1016\/J.BMCL.2015.01.001","article-title":"Synthesis and SAR study of potent and selective PI3K\u03b4 inhibitors","volume":"25","author":"Bui","year":"2015","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"B13","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1186\/S12902-025-02007-X","article-title":"The relationship between pan-immune inflammation value and different stages of diabetic retinopathy in patients with type 2 diabetes mellitus: a prospective cross-sectional study","volume":"25","author":"Bulu","year":"2025","journal-title":"BMC Endocr. Disord."},{"key":"B14","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/J.JAIP.2023.09.016","article-title":"PI3K\u03b4 pathway dysregulation and unique features of its inhibition by Leniolisib in activated PI3K\u03b4 syndrome and beyond","volume":"12","author":"Cant","year":"2024","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"B15","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1080\/1062936X.2014.883428","article-title":"Imidazo[1,2-a]pyrazine inhibitors of phosphoinositide 3-kinase alpha (PI3K\u03b1): 3D-QSAR analysis utilizing the Hybrid Monte Carlo algorithm to refine receptor-ligand complexes for molecular alignment","volume":"25","author":"Chadha","year":"2014","journal-title":"Sar. QSAR Environ. Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"12754","DOI":"10.1038\/s41598-023-39473-z","article-title":"Downregulation of PIK3IP1 in retinal microglia promotes retinal pathological neovascularization via PI3K-AKT pathway activation","volume":"13","author":"Chen","year":"2023","journal-title":"Sci. Rep."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.7554\/ELIFE.59151","article-title":"The structural determinants of PH domain-mediated regulation of Akt revealed by segmental labeling","volume":"9","author":"Chu","year":"2020","journal-title":"Elife"},{"key":"B18","doi-asserted-by":"publisher","first-page":"6062","DOI":"10.1021\/ACS.MOLPHARMACEUT.4C00725","article-title":"From preformulative design to in vivo tests: a complex path of requisites and studies for nanoparticle ocular application. Part 2: in vitro,, Ex Vivo, and in vivo studies","volume":"21","author":"Cimino","year":"2024","journal-title":"Mol. Pharm."},{"key":"B19","doi-asserted-by":"publisher","first-page":"177323","DOI":"10.1016\/J.EJPHAR.2025.177323","article-title":"Retinal pharmacodynamic and pharmacokinetic profile of cannabidiol in an in vivo model of retinal excitotoxicity","volume":"991","author":"Conti","year":"2025","journal-title":"Eur. J. Pharmacol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1038\/S41420-023-01545-4","article-title":"Aberrant Akt2 signaling in the RPE may contribute to retinal fibrosis process in diabetic retinopathy","volume":"9","author":"Daley","year":"2023","journal-title":"Cell Death Discov."},{"key":"B21","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1111\/J.1469-8986.1990.TB00378.X","article-title":"Psychophysiology at the interface of clinical science, cognitive science, and neuroscience","volume":"27","author":"Dawson","year":"1990","journal-title":"Psychophysiology"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2003264","article-title":"G protein-coupled receptor-mediated activation of p110b by G\u03b2\u03b3 is required for cellular transformation and invasiveness","volume":"5","author":"Dbouk","year":"2012","journal-title":"Sci. Signal."},{"key":"B23","doi-asserted-by":"publisher","first-page":"4773","DOI":"10.1016\/J.BMCL.2011.06.063","article-title":"Identification of 2-oxatriazines as highly potent pan-PI3K\/mTOR dual inhibitors","volume":"21","author":"Dehnhardt","year":"2011","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"B24","doi-asserted-by":"publisher","first-page":"2979","DOI":"10.4049\/JIMMUNOL.2000326","article-title":"Seletalisib for activated PI3K\u03b4 syndromes: Open-Label phase 1b and extension studies","volume":"205","author":"Diaz","year":"2020","journal-title":"J. Immunol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1789","DOI":"10.1021\/JM1014605\/SUPPL_FILE\/JM1014605_SI_001","article-title":"Discovery and optimization of a series of benzothiazole phosphoinositide 3-kinase (PI3K)\/mammalian target of rapamycin (mTOR) dual inhibitors","volume":"54","author":"D\u2019Angelo","year":"2011","journal-title":"J. Med. Chem."},{"key":"B26","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1161\/CIRCULATIONAHA.119.042354","article-title":"Phosphoinositide 3-Kinase-Regulated pericyte maturation governs vascular remodeling","volume":"142","author":"Figueiredo","year":"2020","journal-title":"Circulation"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1397","DOI":"10.1042\/BST20190845","article-title":"Class IA PI3K regulatory subunits: p110-independent roles and structures","volume":"48","author":"Fox","year":"2020","journal-title":"Biochem. Soc. Trans."},{"key":"B28","doi-asserted-by":"publisher","first-page":"128046","DOI":"10.1016\/J.BMCL.2021.128046","article-title":"Discovery of a new series of PI3K-\u03b4 inhibitors from Virtual Screening","volume":"42","author":"Fradera","year":"2021","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"B29","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1021\/ci700348m","article-title":"Phosphoinositide-3-kinases (PI3Ks): combined comparative modeling and 3D-QSAR to rationalize the inhibition of p110\u03b1","volume":"48","author":"Fr\u00e9d\u00e9rick","year":"2008","journal-title":"J. Chem. Inf. Model."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1002\/BKCS.12305","article-title":"Computational modeling of novel Phosphoinositol-3-kinase \u03b3 inhibitors using molecular docking, molecular dynamics, and 3D-QSAR","volume":"42","author":"Ghosh","year":"2021","journal-title":"Bull. Korean Chem. Soc."},{"key":"B31","doi-asserted-by":"publisher","first-page":"D1045","DOI":"10.1093\/NAR\/GKV1072","article-title":"BindingDB in 2015: a public database for medicinal chemistry, computational chemistry and systems pharmacology","volume":"44","author":"Gilson","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"B32","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1038\/NATURE06892","article-title":"Angiogenesis selectively requires the p110\u03b1 isoform of PI3K to control endothelial cell migration","volume":"453","author":"Graupera","year":"2008","journal-title":"Nature"},{"key":"B33","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1016\/J.TCB.2019.01.001","article-title":"Class II PI3K functions in cell biology and disease","volume":"29","author":"Gulluni","year":"2019","journal-title":"Trends Cell Biol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1007\/S10792-025-03870-2","article-title":"The blood-retinal barrier in ocular pathologies: an updated narrative review","volume":"46","author":"Hang","year":"2025","journal-title":"Int. Ophthalmol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"157004","DOI":"10.1016\/J.CYTO.2025.157004","article-title":"Effect of cytokine TGF-\u03b21 on pathological changes in diabetic retinopathy","volume":"194","author":"Hartmane","year":"2025","journal-title":"Cytokine"},{"key":"B36","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1007\/82_2010_40","article-title":"PI3K signaling in neutrophils","volume":"346","author":"Hawkins","year":"2010"},{"key":"B37","doi-asserted-by":"publisher","first-page":"6847","DOI":"10.1016\/J.BMC.2006.06.046","article-title":"Synthesis and biological evaluation of 4-morpholino-2-phenylquinazolines and related derivatives as novel PI3 kinase p110\u03b1 inhibitors","volume":"14","author":"Hayakawa","year":"2006","journal-title":"Bioorg. Med. Chem."},{"key":"B38","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1016\/J.BMC.2006.09.047","article-title":"Synthesis and biological evaluation of imidazo[1,2-a]pyridine derivatives as novel PI3 kinase p110\u03b1 inhibitors","volume":"15","author":"Hayakawa","year":"","journal-title":"Bioorg. Med. Chem."},{"key":"B39","doi-asserted-by":"publisher","first-page":"2438","DOI":"10.1016\/J.BMCL.2007.02.032","article-title":"Synthesis and biological evaluation of pyrido[3\u2032,2\u2032:4,5]furo[3,2-d]pyrimidine derivatives as novel PI3 kinase p110\u03b1 inhibitors","volume":"17","author":"Hayakawa","year":"","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"B40","doi-asserted-by":"publisher","first-page":"5837","DOI":"10.1016\/J.BMC.2007.05.070","article-title":"Synthesis and biological evaluation of sulfonylhydrazone-substituted imidazo[1,2-a]pyridines as novel PI3 kinase p110\u03b1 inhibitors","volume":"15","author":"Hayakawa","year":"","journal-title":"Bioorg. Med. Chem."},{"key":"B41","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1007\/s00228-017-2205-7","article-title":"First-in-human studies of seletalisib, an orally bioavailable small-molecule PI3K\u03b4 inhibitor for the treatment of immune and inflammatory diseases","volume":"73","author":"Helmer","year":"2017","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1364","DOI":"10.1093\/RHEUMATOLOGY\/KEAA410","article-title":"A phase 2 randomized, double-blind, placebo-controlled, proof-of-concept study of oral seletalisib in primary Sj\u00f6gren\u2019s syndrome","volume":"60","author":"Juarez","year":"2021","journal-title":"Rheumatology"},{"key":"B43","doi-asserted-by":"publisher","first-page":"e184465","DOI":"10.1172\/JCI.INSIGHT.184465","article-title":"Immunomodulation of inflammatory responses preserves retinal integrity in murine models of pericyte-depletion retinopathy","volume":"10","author":"Kinuthia","year":"2025","journal-title":"JCI Insight"},{"key":"B44","doi-asserted-by":"publisher","first-page":"4213","DOI":"10.1172\/JCI65157","article-title":"Targeted deletion of Vegfa in adult mice induces vision loss","volume":"122","author":"Kurihara","year":"2012","journal-title":"J. Clin. Invest."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1357","DOI":"10.1021\/acs.jcim.4c02153","article-title":"Rationalizing predictions of isoform-selective phosphoinositide 3-Kinase inhibitors using MolAnchor analysis","volume":"65","author":"Lamens","year":"2025","journal-title":"J. Chem. Inf. Model."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1422","DOI":"10.1038\/S41590-024-01890-1","article-title":"PI3K\u03b3 in B cells promotes antibody responses and generation of antibody-secreting cells","volume":"25","author":"Lanahan","year":"2024","journal-title":"Nat. Immunol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/J.BCP.2019.07.021","article-title":"Aflibercept regulates retinal inflammation elicited by high glucose via the PlGF\/ERK pathway","volume":"168","author":"Lazzara","year":"2019","journal-title":"Biochem. Pharmacol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"543310","DOI":"10.3389\/fphar.2020.01063","article-title":"Stabilization of HIF-1\u03b1 in human retinal endothelial cells modulates expression of miRNAs and proangiogenic growth factors","volume":"11","author":"Lazzara","year":"2020","journal-title":"Front. Pharmacol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1449","DOI":"10.1007\/s00894-010-0659-y","article-title":"Pharmacophore modeling and 3D-QSAR analysis of phosphoinositide 3-kinase p110\u03b1 inhibitors","volume":"16","author":"Li","year":"2010","journal-title":"J. Mol. Model."},{"key":"B50","doi-asserted-by":"publisher","first-page":"e1900105","DOI":"10.1002\/CBDV.201900105","article-title":"Rational design of novel phosphoinositide 3-Kinase gamma (PI3K\u03b3) selective inhibitors: a computational investigation integrating 3D-QSAR, molecular docking and molecular dynamics simulation","volume":"16","author":"Li","year":"2019","journal-title":"Chem. Biodivers."},{"key":"B51","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1038\/s41420-023-01717-2","article-title":"Mechanistic insights into the alterations and regulation of the AKT signaling pathway in diabetic retinopathy","volume":"9","author":"Li","year":"2023","journal-title":"Cell Death Discov. 2023"},{"key":"B52","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1021\/ml300045b","article-title":"Rational design, synthesis, and SAR of a novel thiazolopyrimidinone series of selective PI3K-beta inhibitors","volume":"3","author":"Lin","year":"2012","journal-title":"ACS Med. Chem. Lett."},{"key":"B53","doi-asserted-by":"publisher","first-page":"102026","DOI":"10.1016\/J.LABINV.2024.102026","article-title":"PI3K\u03b4 mediates fibrosis by patient-derived vitreous","volume":"104","author":"Liu","year":"2024","journal-title":"Lab. Investig."},{"key":"B54","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/J.EJMECH.2015.05.025","article-title":"Design, synthesis and biological evaluation of novel 4-alkynyl-quinoline derivatives as PI3K\/mTOR dual inhibitors","volume":"99","author":"Lv","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"B55","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1016\/J.MOLMED.2018.08.003","article-title":"Cancer-Associated PIK3CA mutations in overgrowth disorders","volume":"24","author":"Madsen","year":"2018","journal-title":"Trends Mol. Med."},{"key":"B56","doi-asserted-by":"publisher","first-page":"89","DOI":"10.18632\/ONCOTARGET.114","article-title":"The Phosphatidylinositol 3-kinase\/AKT\/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients","volume":"1","author":"Martelli","year":"2010","journal-title":"Oncotarget"},{"key":"B57","doi-asserted-by":"publisher","first-page":"1874","DOI":"10.1016\/J.BMCL.2012.01.074","article-title":"Imidazo[1,2-a]pyrazines as novel PI3K inhibitors","volume":"22","author":"Mart\u00ednez Gonz\u00e1lez","year":"","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"B58","doi-asserted-by":"publisher","first-page":"3460","DOI":"10.1016\/J.BMCL.2012.03.090","article-title":"Identification of ETP-46321, a potent and orally bioavailable PI3K \u03b1, \u03b4 inhibitor","volume":"22","author":"Mart\u00ednez Gonz\u00e1lez","year":"","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"B59","doi-asserted-by":"publisher","first-page":"7686","DOI":"10.1021\/jm300717c","article-title":"Potent and highly selective benzimidazole inhibitors of PI3-kinase delta","volume":"55","author":"Murray","year":"2012","journal-title":"J. Med. Chem."},{"key":"B60","doi-asserted-by":"publisher","first-page":"4735","DOI":"10.1021\/jm200386s","article-title":"Phospshoinositide 3-kinase (PI3K)\/mammalian target of rapamycin (mTOR) dual inhibitors: discovery and structure-activity relationships of a series of quinoline and quinoxaline derivatives","volume":"54","author":"Nishimura","year":"2011","journal-title":"J. Med. Chem."},{"key":"B61","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/J.GENE.2019.02.076","article-title":"The relation between PI3K\/AKT signalling pathway and cancer","volume":"698","author":"Noorolyai","year":"2019","journal-title":"Gene"},{"key":"B62","doi-asserted-by":"publisher","first-page":"292","DOI":"10.2174\/1386207320666170427143858","article-title":"3D-QSAR, virtual screening, docking and design of dual PI3K\/mTOR inhibitors with enhanced antiproliferative activity","volume":"20","author":"Olui\u0107","year":"2017","journal-title":"Comb. Chem. High. Throughput Screen."},{"key":"B63","doi-asserted-by":"publisher","first-page":"2477","DOI":"10.1074\/JBC.272.4.2477","article-title":"Characterization of p150, an adaptor protein for the human phosphatidylinositol (PtdIns) 3-Kinase","volume":"272","author":"Panaretou","year":"1997","journal-title":"J. Biol. Chem."},{"key":"B64","doi-asserted-by":"publisher","first-page":"1753","DOI":"10.1007\/s11224-018-1154-9","article-title":"Discovery and design of new PI3K inhibitors through pharmacophore-based virtual screening, molecular docking, and binding free energy analysis","volume":"29","author":"Peddi","year":"2018","journal-title":"Struct. Chem."},{"key":"B65","doi-asserted-by":"publisher","first-page":"56344","DOI":"10.1039\/C7RA10870B","article-title":"Molecular modeling studies of quinazolinone derivatives as novel PI3K\u03b4 selective inhibitors","volume":"7","author":"Peng","year":"2017","journal-title":"RSC Adv."},{"key":"B66","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/J.BCP.2018.09.016","article-title":"Computational systems biology approach to identify novel pharmacological targets for diabetic retinopathy","volume":"158","author":"Platania","year":"2018","journal-title":"Biochem. Pharmacol."},{"key":"B67","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1080\/10717544.2019.1574936","article-title":"Novel ophthalmic formulation of myriocin: implications in retinitis pigmentosa","volume":"26","author":"Platania","year":"2019","journal-title":"Drug Deliv."},{"key":"B68","doi-asserted-by":"publisher","first-page":"3849","DOI":"10.1172\/JCI65509","article-title":"Turning a blind eye to anti-VEGF toxicities","volume":"122","author":"Quaggin","year":"2012","journal-title":"J. Clin. Invest."},{"key":"B69","doi-asserted-by":"publisher","first-page":"e64691","DOI":"10.7554\/ELIFE.64691","article-title":"Disease-related mutations in PI3K\u03b3 disrupt regulatory c-terminal dynamics and reveal a path to selective inhibitors","volume":"10","author":"Rathinaswamy","year":"2021","journal-title":"Elife"},{"key":"B70","doi-asserted-by":"publisher","first-page":"112172","DOI":"10.1016\/J.CELREP.2023.112172","article-title":"Molecular basis for differential activation of p101 and p84 complexes of PI3K\u03b3 by Ras and GPCRs","volume":"42","author":"Rathinaswamy","year":"2023","journal-title":"Cell Rep."},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-09843-0","article-title":"QSAR analysis on a large and diverse set of potent phosphoinositide 3-kinase gamma (PI3K\u03b3) inhibitors using MLR and ANN methods","volume":"12","author":"Sadeghi","year":"2022","journal-title":"Sci. Rep. 2022"},{"key":"B72","doi-asserted-by":"publisher","first-page":"175827","DOI":"10.1016\/J.EJPHAR.2023.175827","article-title":"Phosphoinositide 3-kinase (PI3K) classes: from cell signaling to endocytic recycling and autophagy","volume":"953","author":"Safaroghli-Azar","year":"2023","journal-title":"Eur. J. Pharmacol."},{"key":"B73","doi-asserted-by":"publisher","first-page":"1587","DOI":"10.1007\/s00044-012-0151-6","article-title":"Quasi 4D-QSAR and 3D-QSAR study of the pan class i phosphoinositide-3- kinase (PI3K) inhibitors","volume":"22","author":"Safavi-Sohi","year":"2013","journal-title":"Med. Chem. Res."},{"key":"B74","doi-asserted-by":"publisher","first-page":"554","DOI":"10.1126\/science.1096502","article-title":"High frequency of mutations of the PIK3CA gene in human cancers","volume":"304","author":"Samuels","year":"2004","journal-title":"Science"},{"key":"B75","doi-asserted-by":"publisher","first-page":"e105280","DOI":"10.1371\/JOURNAL.PONE.0105280","article-title":"Deciphering combinations of PI3K\/AKT\/mTOR pathway drugs augmenting anti-angiogenic efficacy in vivo","volume":"9","author":"Sasore","year":"2014","journal-title":"PLoS One"},{"key":"B76","doi-asserted-by":"publisher","first-page":"1517","DOI":"10.1002\/CMDC.201600148","article-title":"Discovery and SAR of Novel 2,3\u2010Dihydroimidazo[1,2\u2010c]quinazoline PI3K inhibitors: identification of Copanlisib (BAY 80\u20106946)","volume":"11","author":"Scott","year":"2016","journal-title":"ChemMedChem"},{"key":"B77","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1167\/IOVS.64.5.28","article-title":"Mechanisms of acquired resistance to Anti-VEGF therapy for neovascular eye diseases","volume":"64","author":"Sharma","year":"2023","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"B78","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1093\/CARCIN\/BGAE059","article-title":"Advanced glycation end products promote the progression of endometrial cancer via activating the RAGE\/CHKA\/PI3K\/AKT signaling pathway","volume":"46","author":"Shu","year":"2025","journal-title":"Carcinogenesis"},{"key":"B79","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1159\/000492924","article-title":"Onset of retinal pigment epithelium atrophy subsequent to Anti-VEGF therapy in patients with neovascular age-related macular degeneration","volume":"241","author":"Sitnilska","year":"2019","journal-title":"Ophthalmologica"},{"key":"B80","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.2337\/DB17-1509","article-title":"Mice carrying a dominant-negative Human PI3K mutation are protected from obesity and hepatic steatosis but not diabetes","volume":"67","author":"Solheim","year":"2018","journal-title":"Diabetes"},{"key":"B81","doi-asserted-by":"publisher","first-page":"5174","DOI":"10.1021\/jm2004442","article-title":"Structure-activity relationships of phosphoinositide 3-kinase (PI3K)\/mammalian target of rapamycin (mTOR) dual inhibitors: investigations of various 6,5-heterocycles to improve metabolic stability","volume":"54","author":"Stec","year":"2011","journal-title":"J. Med. Chem."},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1007\/S10822-025-00621-4","article-title":"A computational study of cardiac glycosides from Vernonia amygdalina as PI3K inhibitors for targeting HER2 positive breast cancer","volume":"39","author":"Tafrihani","year":"2025","journal-title":"J. Computer-Aided Mol. Des. 2025"},{"key":"B83","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1016\/J.EJMECH.2014.07.056","article-title":"Discovery of nanomolar phosphoinositide 3-kinase gamma (PI3K\u03b3) inhibitors using ligand-based modeling and virtual screening followed by in vitro analysis","volume":"84","author":"Taha","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"B84","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.1002\/CBIN.12189","article-title":"The PI3K\/Akt signaling axis and type 2 diabetes mellitus (T2DM): from mechanistic insights into possible therapeutic targets","volume":"48","author":"Taheri","year":"2024","journal-title":"Cell Biol. Int."},{"key":"B85","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1007\/s10822-016-9905-4","article-title":"Structural insights of a PI3K\/mTOR dual inhibitor with the morpholino-triazine scaffold","volume":"30","author":"Takeda","year":"2016","journal-title":"J. Comput. Aided. Mol. Des."},{"key":"B86","doi-asserted-by":"publisher","first-page":"e13435","DOI":"10.1111\/CPR.13435","article-title":"TGF-\u03b2-induced PI3K\/AKT\/mTOR pathway controls myofibroblast differentiation and secretory phenotype of valvular interstitial cells through the modulation of cellular senescence in a naturally occurring in vitro canine model of myxomatous mitral valve disease","volume":"56","author":"Tang","year":"2023","journal-title":"Cell Prolif."},{"key":"B87","doi-asserted-by":"publisher","first-page":"1598","DOI":"10.3390\/CANCERS14071598","article-title":"Management strategies for hyperglycemia associated with the \u03b1-Selective PI3K inhibitor alpelisib for the treatment of breast cancer","volume":"14","author":"Tankova","year":"2022","journal-title":"Cancers"},{"key":"B88","doi-asserted-by":"publisher","first-page":"8","DOI":"10.53151\/2531-3916\/2024-588","article-title":"PI3K\u03b4 inhibition treatment of APDS: efficacy, safety and tolerability of targeted therapy with leniolisib","volume":"38","author":"Tommasini","year":"2024","journal-title":"Italian J. Pediatr. Allergy Immunol."},{"key":"B89","doi-asserted-by":"publisher","first-page":"27975","DOI":"10.1074\/jbc.M204152200","article-title":"Insulin stimulates hypoxia-inducible factor 1 through a phosphatidylinositol 3-kinase\/target of rapamycin-dependent signaling pathway","volume":"277","author":"Treins","year":"2002","journal-title":"J. Biol. Chem."},{"key":"B90","doi-asserted-by":"publisher","first-page":"18862","DOI":"10.1073\/pnas.1304801110","article-title":"Molecular determinants of PI3K\u03b3-mediated activation downstream of G-protein-coupled receptors (GPCRs)","volume":"110","author":"Vadas","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B91","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1016\/J.TIBS.2005.02.008","article-title":"Signalling by PI3K isoforms: insights from gene-targeted mice","volume":"30","author":"Vanhaesebroeck","year":"2005","journal-title":"Trends biochem. Sci."},{"key":"B92","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1124\/pharmrev.123.001015","article-title":"The role of G protein\u2013coupled receptors and receptor kinases in pancreatic \u03b2-Cell function and diabetes","volume":"76","author":"Varney","year":"2024","journal-title":"Pharmacol. Rev."},{"key":"B93","doi-asserted-by":"publisher","first-page":"2636","DOI":"10.1021\/jm901830p","article-title":"Bis(morpholino-l,3,5-triazine) derivatives: potent adenosine 5\u2032-triphosphate competitive phosphatidylinositol-3-kinase\/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor","volume":"53","author":"Venkatesan","year":"2010","journal-title":"J. Med. Chem."},{"key":"B94","doi-asserted-by":"publisher","first-page":"8010","DOI":"10.1021\/jm9013828","article-title":"Discovery of 4-morpholino-6-aryl-1H-pyrazolo[3,4-d]pyrimidines as highly potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): optimization of the 6-aryl substituent","volume":"52","author":"Verheijen","year":"2009","journal-title":"J. Med. Chem."},{"key":"B95","doi-asserted-by":"publisher","first-page":"2943","DOI":"10.1007\/s00894-011-1299-6","article-title":"Molecular simulation of a series of benzothiazole PI3K\u03b1 inhibitors: probing the relationship between structural features, anti-tumor potency and selectivity","volume":"18","author":"Wang","year":"2012","journal-title":"J. Mol. Model."},{"key":"B96","doi-asserted-by":"publisher","first-page":"2771","DOI":"10.1038\/s41598-023-29639-0","article-title":"The spatial distribution of GPCR and G\u03b2\u03b3 activity across a cell dictates PIP3 dynamics","volume":"13","author":"Wijayaratna","year":"2023","journal-title":"Sci. Rep. 2023"},{"key":"B97","doi-asserted-by":"publisher","first-page":"17","DOI":"10.5603\/EP.2014.0003","article-title":"The association of leukocyte phosphatidylinositol 3-kinase delta overexpression with gestational diabetes mellitus (GDM)","volume":"65","author":"W\u00f3jcik","year":"2014","journal-title":"Endokrynol. Pol."},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.12","article-title":"Diabetic retinopathy","volume":"2","author":"Wong","year":"2016","journal-title":"Nat. Rev. Dis. Prim. 2016"},{"key":"B99","doi-asserted-by":"publisher","first-page":"736","DOI":"10.2337\/DB19-0713","article-title":"PI3K\u03b4 as a novel therapeutic target in pathological angiogenesis","volume":"69","author":"Wu","year":"2020","journal-title":"Diabetes"},{"key":"B100","doi-asserted-by":"publisher","first-page":"3848","DOI":"10.1097\/JS9.0000000000001289","article-title":"Current perspectives and trend of computer-aided drug design: a review and bibliometric analysis","volume":"110","author":"Wu","year":"2024","journal-title":"Int. J. Surg."},{"key":"B101","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1111\/J.1349-7006.1993.TB00161.X","article-title":"Ductectatic-type mucinous cystadenoma and cystadenocarcinoma of the human pancreas: a novel clinicopathological entity","volume":"84","author":"Yanagisawa","year":"1993","journal-title":"Jpn. J. Cancer Res."},{"key":"B102","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/J.MOLSTRUC.2013.09.049","article-title":"3D-QSAR and docking studies of 3-Pyridine heterocyclic derivatives as potent PI3K\/mTOR inhibitors","author":"Yang","year":"2013","journal-title":"J. Mol. Struct."},{"key":"B103","doi-asserted-by":"publisher","first-page":"1079217","DOI":"10.3389\/fendo.2022.1079217","article-title":"Classification of diabetic retinopathy: past, present and future","volume":"13","author":"Yang","year":"2022","journal-title":"Front. Endocrinol. (Lausanne)."},{"key":"B104","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1007\/978-1-4939-6634-9_5","article-title":"Computer-Aided drug design methods","volume":"1520","author":"Yu","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"B105","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1007\/S10822-017-0092-8\/METRICS","article-title":"Discovering new PI3K\u03b1 inhibitors with a strategy of combining ligand-based and structure-based virtual screening","volume":"32","author":"Yu","year":"2018","journal-title":"J. Comput. Aided. Mol. Des."},{"key":"B106","doi-asserted-by":"publisher","first-page":"7942","DOI":"10.1021\/jm901415x","article-title":"Morpholine derivatives greatly enhance the selectivity of mammalian target of rapamycin (mTOR) inhibitors","volume":"52","author":"Zask","year":"2009","journal-title":"J. Med. Chem."},{"key":"B107","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1016\/J.EJMECH.2017.01.016","article-title":"Discovery of a series of N-(5-(quinolin-6-yl)pyridin-3-yl)benzenesulfonamides as PI3K\/mTOR dual inhibitors","volume":"127","author":"Zhang","year":"","journal-title":"Eur. J. Med. Chem."},{"key":"B108","doi-asserted-by":"publisher","first-page":"2342","DOI":"10.1039\/C6RA26971K","article-title":"Identification of 3-amidoquinoline derivatives as PI3K\/mTOR dual inhibitors with potential for cancer therapy","volume":"7","author":"Zhang","year":"","journal-title":"RSC Adv."},{"key":"B109","doi-asserted-by":"publisher","first-page":"5486","DOI":"10.1038\/onc.2008.244","article-title":"Class I PI3K in oncogenic cellular transformation","volume":"27","author":"Zhao","year":"2008","journal-title":"Oncogene"},{"key":"B110","doi-asserted-by":"publisher","first-page":"8172","DOI":"10.1080\/07391102.2023.2246569","article-title":"Molecular modeling strategy for detailing the primary mechanism of action of copanlisib to PI3K: combined ligand-based and target-based approach","volume":"42","author":"Zhu","year":"2024","journal-title":"J. Biomol. Struct. Dyn."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1744181\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T08:37:36Z","timestamp":1773391056000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1744181\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,13]]},"references-count":110,"alternative-id":["10.3389\/fphar.2026.1744181"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1744181","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,13]]},"article-number":"1744181"}}