{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T08:32:26Z","timestamp":1768465946297,"version":"3.49.0"},"reference-count":41,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2021,7,19]],"date-time":"2021-07-19T00:00:00Z","timestamp":1626652800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology, Taiwan","award":["MOST 109-2320-B-038 -040 -MY3"],"award-info":[{"award-number":["MOST 109-2320-B-038 -040 -MY3"]}]},{"name":"Ministry of Education","award":["DP2-110-21121-01-N-06-03"],"award-info":[{"award-number":["DP2-110-21121-01-N-06-03"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Age-related macular degeneration (AMD) occurs due to an abnormality of retinal pigment epithelium (RPE) cells that leads to gradual degeneration of the macula. Currently, AMD drug pipelines are endowed with limited options, and anti-VEGF agents stand as the dominantly employed therapy. Despite the proven efficacy of such agents, the evidenced side effects associated with their use underscore the need to elucidate other mechanisms involved and identify additional molecular targets for the sake of therapy improvement. The previous literature provided us with a solid rationale to preliminarily explore the potential of selective HDAC6 and HSP90 inhibitors to treat wet AMD. Rather than furnishing single-target agents (either HDAC6 or HSP90 inhibitor), this study recruited scaffolds endowed with the ability to concomitantly modulate both targets (HDAC6 and HSP90) for exploration. This plan was anticipated to accomplish the important goal of extracting amplified benefits via dual inhibition (HDAC6\/HSP90) in wet AMD. As a result, G570 (indoline-based hydroxamate), a dual selective HDAC6-HSP90 inhibitor exerting its effects at micromolar concentrations, was pinpointed in the present endeavor to attenuate blue light-induced cell migration and retinal neovascularization by inhibiting VEGF production. In addition to the identification of a potential chemical tool (G570), the outcome of this study validates the candidate HDAC6-HSP90 as a compelling target for the development of futuristic therapeutics for wet AMD.<\/jats:p>","DOI":"10.3390\/molecules26144359","type":"journal-article","created":{"date-parts":[[2021,7,19]],"date-time":"2021-07-19T10:07:37Z","timestamp":1626689257000},"page":"4359","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The HDAC\/HSP90 Inhibitor G570 Attenuated Blue Light-Induced Cell Migration in RPE Cells and Neovascularization in Mice through Decreased VEGF Production"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8122-3481","authenticated-orcid":false,"given":"Tai-Ju","family":"Hsu","sequence":"first","affiliation":[{"name":"School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 100301, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kunal","family":"Nepali","sequence":"additional","affiliation":[{"name":"School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 100301, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chi-Hao","family":"Tsai","sequence":"additional","affiliation":[{"name":"School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 100301, Taiwan"},{"name":"Department of Ophthalmology, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zuha","family":"Imtiyaz","sequence":"additional","affiliation":[{"name":"School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 100301, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8348-9873","authenticated-orcid":false,"given":"Fan-Li","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 100301, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9079-3646","authenticated-orcid":false,"given":"George","family":"Hsiao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 100301, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mei-Jung","family":"Lai","sequence":"additional","affiliation":[{"name":"Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei 100301, Taiwan"},{"name":"Biomedical Commercialization Center, Taipei Medical University, Taipei 100301, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3714-0464","authenticated-orcid":false,"given":"Yu-Wen","family":"Cheng","sequence":"additional","affiliation":[{"name":"School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 100301, Taiwan"},{"name":"Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei 100301, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.survophthal.2006.05.001","article-title":"The genetics of age-related macular degeneration: A review of progress to date","volume":"51","author":"Haddad","year":"2006","journal-title":"Surv. Ophthalmol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/nrn2007","article-title":"Macular degeneration: Recent advances and therapeutic opportunities","volume":"7","author":"Rattner","year":"2006","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"10533","DOI":"10.1021\/acs.jmedchem.9b01033","article-title":"Ocular disease therapeutics: Design and delivery of drugs for diseases of the eye","volume":"63","author":"Cheng","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1016\/S0140-6736(18)31550-2","article-title":"Age-related macular degeneration","volume":"392","author":"Mitchell","year":"2018","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1038\/nrd3745","article-title":"Ophthalmic drug discovery: Novel targets and mechanisms for retinal diseases and glaucoma","volume":"11","author":"Zhang","year":"2012","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"14682","DOI":"10.1073\/pnas.222551899","article-title":"Drusen proteome analysis: An approach to the etiology of age-related macular degeneration","volume":"99","author":"Crabb","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","first-page":"443","article-title":"The relationships of age changes in retinal pigment epithelium and Bruch\u2019s membrane","volume":"40","author":"Okubo","year":"1999","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1038\/nm1010-1107","article-title":"Vascular endothelial growth factor and age-related macular degeneration: From basic science to therapy","volume":"16","author":"Ferrara","year":"2010","journal-title":"Nat. Med."},{"key":"ref_9","first-page":"116","article-title":"TNF-\u03b1 mediates choroidal neovascularization by upregulating VEGF expression in RPE through ROS-dependent \u03b2-catenin activation","volume":"22","author":"Wang","year":"2016","journal-title":"Mol. Vis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1007\/s00417-017-3711-0","article-title":"Hypoxia and inflammation in the release of VEGF and interleukins from human retinal pigment epithelial cells","volume":"255","author":"Arjamaa","year":"2017","journal-title":"Graefe\u2019s Arch. Clin. Exp. Ophthalmol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1007\/s00018-019-03422-9","article-title":"The role of hypoxia-inducible factors in neovascular age-related macular degeneration: A gene therapy perspective","volume":"77","author":"Mammadzada","year":"2020","journal-title":"Cell Mol. Life Sci."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ju, Y., Tang, Z., Dai, X., Gao, H., Zhang, J., Liu, Y., Yang, Y., Ni, N., Zhang, D., and Wang, Y. (2020). Protection against light-induced retinal degeneration via dual anti-inflammatory and anti-angiogenic functions of thrombospondin-1. Br. J. Pharmacol.","DOI":"10.1111\/bph.15303"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.exer.2015.01.003","article-title":"Blue light-induced inflammatory marker expression in the retinal pigment epithelium-choroid of mice and the protective effect of yellow intraocular lens material in vivo","volume":"132","author":"Narimatsu","year":"2015","journal-title":"Exp. Eye Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1038\/eye.2013.107","article-title":"Adverse events and complications associated with intravitreal injection of anti-VEGF agents: A review of the literature","volume":"27","author":"Falavarjani","year":"2013","journal-title":"Eye"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1089\/jop.2018.0019","article-title":"Oral anti-vascular endothelial growth factor drugs and ocular adverse events","volume":"34","author":"Fraunfelder","year":"2018","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1001\/archopthalmol.2011.1423","article-title":"The potential role of epigenetics in ocular diseases","volume":"130","author":"Nickells","year":"2012","journal-title":"Arch. Ophthalmol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"144","DOI":"10.3389\/fgene.2017.00144","article-title":"Epigenetics in the eye: An overview of the most relevant ocular diseases","volume":"8","author":"Alkozi","year":"2017","journal-title":"Front. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3639","DOI":"10.1167\/iovs.09-4538","article-title":"Inhibition of histone deacetylase protects the retina from ischemic injury","volume":"51","author":"Crosson","year":"2010","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Samardzija, M., Corna, A., Gomez-Sintes, R., Jarboui, M.A., Armento, A., Roger, J.E., Petridou, E., Haq, W., Paquet-Durand, F., and Zrenner, E. (2020). HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice. Cell Death Differ., 1\u201316.","DOI":"10.1101\/2019.12.13.874339"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Dahbash, M., Sella, R., Megiddo-Barnir, E., Nisgav, Y., Tarasenko, N., Weinberger, D., Rephaeli, A., and Livnat, T. (2019). The histone deacetylase inhibitor AN7, attenuates choroidal neovascularization in a mouse model. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030714"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e3028","DOI":"10.1038\/cddis.2017.415","article-title":"HDAC6 inhibition by tubastatin A is protective against oxidative stress in a photoreceptor cell line and restores visual function in a zebrafish model of inherited blindness","volume":"8","author":"Leyk","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"689","DOI":"10.3389\/fcell.2020.00689","article-title":"Selective histone deacetylase 6 inhibitors restore cone photoreceptor vision or outer segment morphology in zebrafish and mouse models of retinal blindness","volume":"8","author":"Sundaramurthi","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2164","DOI":"10.1093\/hmg\/ddt613","article-title":"Hsp90 inhibition protects against inherited retinal degeneration","volume":"23","author":"Aguila","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1016\/j.febslet.2013.05.020","article-title":"The cell stress machinery and retinal degeneration","volume":"587","author":"Athanasiou","year":"2013","journal-title":"FEBS Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/978-3-319-17121-0_22","article-title":"Hsp90 as a potential therapeutic target in retinal disease","volume":"854","author":"LaVail","year":"2016","journal-title":"Retinal Degenerative Diseases"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.exer.2007.08.005","article-title":"Geldanamycin, a HSP90 inhibitor, attenuates the hypoxia-induced vascular endothelial growth factor expression in retinal pigment epithelium cells in vitro","volume":"85","author":"Wu","year":"2007","journal-title":"Exp. Eye Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.ejmech.2018.10.068","article-title":"Enhancement of the tail hydrophobic interactions within the carbonic anhydrase IX active site via structural extension: Design and synthesis of novel N-substituted isatins-SLC-0111 hybrids as carbonic anhydrase inhibitors and antitumor agents","volume":"162","author":"Eldehna","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"12406","DOI":"10.1038\/s41598-017-12795-5","article-title":"Identification of 7-(4\u2032-Cyanophenyl) indoline-1-benzenesulfonamide as a mitotic inhibitor to induce apoptotic cell death and inhibit autophagy in human colorectal cancer cells","volume":"7","author":"Wu","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4953","DOI":"10.1200\/JCO.2010.30.8338","article-title":"Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non\u2013small-cell lung cancer","volume":"28","author":"Sequist","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.jtho.2017.11.131","article-title":"Phase 2 Study of the HSP-90 Inhibitor AUY922 in previously treated and molecularly defined patients with advanced non\u2013small cell lung cancer","volume":"13","author":"Felip","year":"2018","journal-title":"J. Thorac. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Goldman, J.W., Raju, R.N., Gordon, G.A., El-Hariry, I., Teofilivici, F., Vukovic, V.M., Bradley, R., Karol, M.D., Chen, Y., and Guo, W. (2013). A first in human, safety, pharmacokinetics, and clinical activity phase I study of once weekly administration of the Hsp90 inhibitor ganetespib (STA-9090) in patients with solid malignancies. BMC Cancer, 13.","DOI":"10.1186\/1471-2407-13-152"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3171","DOI":"10.1021\/acs.jmedchem.8b00189","article-title":"Kinase and histone deacetylase hybrid inhibitors for cancer therapy","volume":"62","author":"Luan","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1002\/lsm.22293","article-title":"Light emitting diode-generated blue light modulates fibrosis characteristics: Fibroblast proliferation, migration speed, and reactive oxygen species generation","volume":"47","author":"Mamalis","year":"2015","journal-title":"Lasers Surg. Med."},{"key":"ref_34","first-page":"524","article-title":"Inhibition of cell proliferation, migration and apoptosis in blue-light illuminated human retinal pigment epithelium cells by down-regulation of HtrA1","volume":"10","author":"Yu","year":"2017","journal-title":"Int. J. Ophthalmol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5708537","DOI":"10.1155\/2018\/5708537","article-title":"Knockdown of fibromodulin inhibits proliferation and migration of RPE cell via the VEGFR2-AKT pathway","volume":"2018","author":"Hu","year":"2018","journal-title":"J. Ophthalmol."},{"key":"ref_36","first-page":"805","article-title":"Differential expression of VEGF-121, VEGF-165 and VEGF-189 in angiomas and squamous cell carcinoma cell lines of the head and neck","volume":"30","author":"Cai","year":"2010","journal-title":"Anticancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4463","DOI":"10.1167\/iovs.03-1201","article-title":"Focal adhesion kinase overexpression induces enhanced pathological retinal angiogenesis","volume":"45","author":"Kornberg","year":"2004","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2550","DOI":"10.1038\/s41598-018-20930-z","article-title":"Nuclear FAK and its kinase activity regulate VEGFR2 transcription in angiogenesis of adult mice","volume":"8","author":"Sun","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Moiseev, R.V., Morrison, P.W.J., Steele, F., and Khutoryanskiy, V.V. (2019). Penetration enhancers in ocular drug delivery. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11070321"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.jconrel.2014.06.043","article-title":"Ocular delivery of macromolecules","volume":"190","author":"Kim","year":"2014","journal-title":"J. Control. Release"},{"key":"ref_41","first-page":"2631","article-title":"Aflibercept shows strong dose-dependency when administered intravitreally in the mouse CNV model","volume":"59","author":"Maciulaitiene","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/14\/4359\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:31:52Z","timestamp":1760164312000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/14\/4359"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,19]]},"references-count":41,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["molecules26144359"],"URL":"https:\/\/doi.org\/10.3390\/molecules26144359","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,19]]}}}