{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T15:44:03Z","timestamp":1776959043681,"version":"3.51.4"},"reference-count":98,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T00:00:00Z","timestamp":1719532800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["U54AA030451"],"award-info":[{"award-number":["U54AA030451"]}]},{"name":"National Institutes of Health","award":["R01MD017405"],"award-info":[{"award-number":["R01MD017405"]}]},{"name":"National Institutes of Health","award":["RCMI U54MD012392"],"award-info":[{"award-number":["RCMI U54MD012392"]}]},{"name":"Golden LEAF Foundation","award":["U54AA030451"],"award-info":[{"award-number":["U54AA030451"]}]},{"name":"Golden LEAF Foundation","award":["R01MD017405"],"award-info":[{"award-number":["R01MD017405"]}]},{"name":"Golden LEAF Foundation","award":["RCMI U54MD012392"],"award-info":[{"award-number":["RCMI U54MD012392"]}]},{"name":"Biomanufacturing Research Institute &amp; Technology Enterprise (BRITE) Center for Excellence at North Carolina Central University","award":["U54AA030451"],"award-info":[{"award-number":["U54AA030451"]}]},{"name":"Biomanufacturing Research Institute &amp; Technology Enterprise (BRITE) Center for Excellence at North Carolina Central University","award":["R01MD017405"],"award-info":[{"award-number":["R01MD017405"]}]},{"name":"Biomanufacturing Research Institute &amp; Technology Enterprise (BRITE) Center for Excellence at North Carolina Central University","award":["RCMI U54MD012392"],"award-info":[{"award-number":["RCMI U54MD012392"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Aberrant activation of hedgehog (Hh) signaling has been implicated in various cancers. Current FDA-approved inhibitors target the seven-transmembrane receptor Smoothened, but resistance to these drugs has been observed. It has been proposed that a more promising strategy to target this pathway is at the GLI1 transcription factor level. GANT61 was the first small molecule identified to directly suppress GLI-mediated activity; however, its development as a potential anti-cancer agent has been hindered by its modest activity and aqueous chemical instability. Our study aimed to identify novel GLI1 inhibitors. JChem searches identified fifty-two compounds similar to GANT61 and its active metabolite, GANT61-D. We combined high-throughput cell-based assays and molecular docking to evaluate these analogs. Five of the fifty-two GANT61 analogs inhibited activity in Hh-responsive C3H10T1\/2 and Gli-reporter NIH3T3 cellular assays without cytotoxicity. Two of the GANT61 analogs, BAS 07019774 and Z27610715, reduced Gli1 mRNA expression in C3H10T1\/2 cells. Treatment with BAS 07019774 significantly reduced cell viability in Hh-dependent glioblastoma and lung cancer cell lines. Molecular docking indicated that BAS 07019774 is predicted to bind to the ZF4 region of GLI1, potentially interfering with its ability to bind DNA. Our findings show promise in developing more effective and potent GLI inhibitors.<\/jats:p>","DOI":"10.3390\/molecules29133095","type":"journal-article","created":{"date-parts":[[2024,7,1]],"date-time":"2024-07-01T08:17:29Z","timestamp":1719821849000},"page":"3095","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Identification of Novel GANT61 Analogs with Activity in Hedgehog Functional Assays and GLI1-Dependent Cancer Cells"],"prefix":"10.3390","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5882-4948","authenticated-orcid":false,"given":"Dina","family":"Abu Rabe","sequence":"first","affiliation":[{"name":"INBS PhD Program, North Carolina Central University, Durham, NC 27707, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lhoucine","family":"Chdid","sequence":"additional","affiliation":[{"name":"Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David R.","family":"Lamson","sequence":"additional","affiliation":[{"name":"Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7492-8720","authenticated-orcid":false,"given":"Christopher P.","family":"Laudeman","sequence":"additional","affiliation":[{"name":"Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Tarpley","sequence":"additional","affiliation":[{"name":"Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naglaa","family":"Elsayed","sequence":"additional","affiliation":[{"name":"Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ginger R.","family":"Smith","sequence":"additional","affiliation":[{"name":"Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9025-7229","authenticated-orcid":false,"given":"Weifan","family":"Zheng","sequence":"additional","affiliation":[{"name":"Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA"},{"name":"Department of Pharmaceutical Sciences, North Carolina Central University, Durham, NC 27707, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0493-4208","authenticated-orcid":false,"given":"Maria S.","family":"Dixon","sequence":"additional","affiliation":[{"name":"Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6930-4630","authenticated-orcid":false,"given":"Kevin P.","family":"Williams","sequence":"additional","affiliation":[{"name":"Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA"},{"name":"Department of Pharmaceutical Sciences, North Carolina Central University, Durham, NC 27707, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1126\/science.3563490","article-title":"Identification of an amplified, highly expressed gene in a human glioma","volume":"236","author":"Kinzler","year":"1987","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1038\/332371a0","article-title":"The GLI gene is a member of the Kruppel family of zinc finger proteins","volume":"332","author":"Kinzler","year":"1988","journal-title":"Nature"},{"key":"ref_3","first-page":"634","article-title":"The GLI gene encodes a nuclear protein which binds specific sequences in the human genome","volume":"10","author":"Kinzler","year":"1990","journal-title":"Mol. Cell. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.ejca.2005.08.039","article-title":"GLI transcription factors: Mediators of oncogenic Hedgehog signalling","volume":"42","author":"Kasper","year":"2006","journal-title":"Eur. J. Cancer"},{"key":"ref_5","first-page":"3104","article-title":"The GLI-Kruppel family of human genes","volume":"8","author":"Ruppert","year":"1988","journal-title":"Mol. Cell. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/bs.ctdb.2022.04.003","article-title":"Hedgehog signaling","volume":"149","author":"Ingham","year":"2022","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0070-2153(03)53002-2","article-title":"Developmental roles and clinical significance of hedgehog signaling","volume":"53","author":"McMahon","year":"2003","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1038\/s41580-023-00591-1","article-title":"Cellular and molecular mechanisms of Hedgehog signalling","volume":"24","author":"Zhang","year":"2023","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/s41392-023-01559-5","article-title":"Hedgehog signaling in tissue homeostasis, cancers, and targeted therapies","volume":"8","author":"Jing","year":"2023","journal-title":"Signal Trans. Targeted Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1038\/nrd2086","article-title":"Targeting the Hedgehog pathway in cancer","volume":"5","author":"Rubin","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Sigafoos, A.N., Paradise, B.D., and Fernandez-Zapico, M.E. (2021). Hedgehog\/GLI signaling pathway: Transduction, regulation, and implications for disease. Cancers, 13.","DOI":"10.3390\/cancers13143410"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1684","DOI":"10.3390\/cancers7030857","article-title":"Non-canonical Hh signaling in cancer\u2014Current understanding and future directions","volume":"7","author":"Gu","year":"2015","journal-title":"Cancers"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1016\/j.cellsig.2009.01.033","article-title":"Hedgehog signalling: Emerging evidence for non-canonical pathways","volume":"21","author":"Jenkins","year":"2009","journal-title":"Cell. Signal."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2458","DOI":"10.4161\/cc.6.20.4808","article-title":"Non-canonical activation of GLI transcription factors: Implications for targeted anti-cancer therapy","volume":"6","author":"Lauth","year":"2007","journal-title":"Cell Cycle"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Pietrobono, S., Gagliardi, S., and Stecca, B. (2019). Non-canonical hedgehog signaling pathway in cancer: Activation of GLI transcription factors beyond smoothened. Front. Genet., 10.","DOI":"10.3389\/fgene.2019.00556"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Suchors, C., and Kim, J. (2022). Canonical hedgehog pathway and noncanonical GLI transcription factor activation in cancer. Cells, 11.","DOI":"10.3390\/cells11162523"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Niewiadomski, P., Niedzi\u00f3\u0142ka, S.M., Markiewicz, \u0141., U\u015bpie\u0144ski, T., Baran, B., and Chojnowska, K. (2019). Gli proteins: Regulation in development and cancer. Cells, 8.","DOI":"10.3390\/cells8020147"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"238","DOI":"10.2174\/138920210791233108","article-title":"The human glioma-associated oncogene homolog 1 (GLI1) family of transcription factors in gene regulation and diseases","volume":"11","author":"Zhu","year":"2010","journal-title":"Curr. Genom."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"558","DOI":"10.2174\/1568009618666171129223533","article-title":"Role of glioma-associated GLI1 oncogene in carcinogenesis and cancer-targeted therapy","volume":"18","author":"Wu","year":"2018","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Avery, J.T., Zhang, R., and Boohaker, R.J. (2021). GLI1: A therapeutic target for cancer. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.673154"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Miller, J.S., and Rhoades, J. (2023). Targeting hedgehog-driven mechanisms of drug-resistant cancers. Front. Mol. Biosci., 10.","DOI":"10.3389\/fmolb.2023.1286090"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6981","DOI":"10.1158\/0008-5472.CAN-07-0491","article-title":"Induction of sonic hedgehog mediators by transforming growth factor-beta: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo","volume":"67","author":"Dennler","year":"2007","journal-title":"Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.ccr.2011.12.028","article-title":"The crosstalk of mTOR\/S6K1 and Hedgehog pathways","volume":"21","author":"Wang","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1038\/nm.3328","article-title":"Coordinate activation of Shh and PI3K signaling in PTEN-deficient glioblastoma: New therapeutic opportunities","volume":"19","author":"Dabral","year":"2013","journal-title":"Nat. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4448","DOI":"10.1158\/0008-5472.CAN-16-3315","article-title":"GLI1 blockade potentiates the antitumor activity of PI3K antagonists in lung squamous cell carcinoma","volume":"77","author":"Kasiri","year":"2017","journal-title":"Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1097\/CAD.0000000000000609","article-title":"Hedgehog pathway and smoothened inhibitors in cancer therapies","volume":"29","author":"Chahal","year":"2018","journal-title":"Anti-Cancer Drugs"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Nicheperovich, A., and Townsend-Nicholson, A. (2022). Towards Precision Oncology: The Role of Smoothened and Its Variants in Cancer. J. Pers. Med., 12.","DOI":"10.20944\/preprints202209.0205.v1"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1007\/s40265-015-0458-y","article-title":"Sonidegib: First global approval","volume":"75","author":"Burness","year":"2015","journal-title":"Drugs"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/s40265-018-1047-7","article-title":"Glasdegib: First global approval","volume":"79","author":"Hoy","year":"2019","journal-title":"Drugs"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1038\/nbt1109-968","article-title":"Genentech obtains proof of concept for hedgehog inhibition","volume":"27","author":"Sheridan","year":"2009","journal-title":"Nat. Biotechnol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.ccell.2015.02.002","article-title":"Smoothened variants explain the majority of drug resistance in basal cell carcinoma","volume":"27","author":"Atwood","year":"2015","journal-title":"Cancer Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.bbcan.2015.06.003","article-title":"Digging a hole under Hedgehog: Downstream inhibition as an emerging anticancer strategy","volume":"1856","author":"Coni","year":"2015","journal-title":"Biochim. Biophys. Acta-Rev. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"13899","DOI":"10.18632\/oncotarget.4224","article-title":"Targeting the Hedgehog signaling pathway in cancer: Beyond Smoothened","volume":"6","author":"Gonnissen","year":"2015","journal-title":"Oncotarget"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.tips.2015.05.006","article-title":"Targeting GLI factors to inhibit the Hedgehog pathway","volume":"36","author":"Infante","year":"2015","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Sabol, M., Trnski, D., Musani, V., Ozreti\u0107, P., and Levanat, S. (2018). Role of GLI transcription factors in pathogenesis and their potential as new therapeutic targets. Intl. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19092562"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Yang, F., Wynn, D.T., Shen, C., Ayad, N.G., and Robbins, D.J. (2022). Multiprotein GLI Transcriptional Complexes as Therapeutic Targets in Cancer. Life, 12.","DOI":"10.3390\/life12121967"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Didiasova, M., Schaefer, L., and Wygrecka, M. (2018). Targeting GLI transcription factors in cancer. Molecules, 23.","DOI":"10.3390\/molecules23051003"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Ruiz i Altaba, A., and Ruiz i Altaba, A. (2006). How the Hedgehog Outfoxed the Crab: Interference with HEDGEHOG-GLI Signaling as Anti-Cancer Therapy?. Madame Curie Bioscience Database, Landes Bioscience.","DOI":"10.1007\/0-387-33777-6"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"200","DOI":"10.15252\/embj.201489213","article-title":"Gli1\/DNA interaction is a druggable target for Hedgehog-dependent tumors","volume":"34","author":"Infante","year":"2015","journal-title":"EMBO J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"8455","DOI":"10.1073\/pnas.0609699104","article-title":"Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists","volume":"104","author":"Lauth","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4492","DOI":"10.18632\/oncotarget.2046","article-title":"Mode and specificity of binding of the small molecule GANT61 to GLI determines inhibition of GLI-DNA binding","volume":"5","author":"Agyeman","year":"2014","journal-title":"Oncotarget"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1158\/0008-5472.CAN-10-2315","article-title":"Hedgehog signaling drives cellular survival in human colon carcinoma cells","volume":"71","author":"Mazumdar","year":"2011","journal-title":"Cancer Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s12964-017-0213-y","article-title":"Involvement of hedgehog pathway in early onset, aggressive molecular subtypes and metastatic potential of breast cancer","volume":"16","author":"Riaz","year":"2018","journal-title":"Cell Commun. Signal."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1002\/ijc.27820","article-title":"Targeting the hedgehog signal transduction pathway at the level of GLI inhibits neuroblastoma cell growth in vitro and in vivo","volume":"132","author":"Wickstrom","year":"2013","journal-title":"Int. J. Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1080\/14756366.2017.1419221","article-title":"Chemical, computational and functional insights into the chemical stability of the Hedgehog pathway inhibitor GANT61","volume":"33","author":"Calcaterra","year":"2018","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1080\/13543776.2020.1730327","article-title":"Hedgehog signaling pathway inhibitors: An updated patent review (2015\u2013present)","volume":"30","author":"Quaglio","year":"2020","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Peer, E., Tesanovic, S., and Aberger, F. (2019). Next-generation Hedgehog\/GLI pathway inhibitors for cancer therapy. Cancers, 11.","DOI":"10.3390\/cancers11040538"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"14132","DOI":"10.1073\/pnas.0907134106","article-title":"Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade","volume":"106","author":"Hyman","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1172\/JCI42874","article-title":"Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog\/GLI pathway","volume":"121","author":"Beauchamp","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s40264-018-0777-5","article-title":"Safety and Tolerability of Sonic Hedgehog Pathway Inhibitors in Cancer","volume":"42","author":"Carpenter","year":"2019","journal-title":"Drug Saf."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1916","DOI":"10.1096\/fj.201600892RR","article-title":"Pirfenidone exerts antifibrotic effects through inhibition of GLI transcription factors","volume":"31","author":"Didiasova","year":"2017","journal-title":"FASEB J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"4811","DOI":"10.1158\/0008-5472.CAN-14-0317","article-title":"Pyrvinium attenuates Hedgehog signaling downstream of smoothened","volume":"74","author":"Li","year":"2014","journal-title":"Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"4277","DOI":"10.1021\/jm900106f","article-title":"Structure\u2212Activity Relationships and Cancer-Cell Selective Toxicity of Novel Inhibitors of Glioma-Associated Oncogene Homologue 1 (Gli1) Mediated Transcription","volume":"52","author":"Mahindroo","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1038\/onc.2013.164","article-title":"Targeting Gli transcription activation by small molecule suppresses tumor growth","volume":"33","author":"Zhang","year":"2014","journal-title":"Oncogene"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1002\/bip.21544","article-title":"A structure\u2013activity relationship study of small-molecule inhibitors of GLI1-mediated transcription","volume":"95","author":"Actis","year":"2011","journal-title":"Biopolymers"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4801","DOI":"10.1016\/j.bmc.2010.05.001","article-title":"Amide conjugates of ketoprofen and indole as inhibitors of Gli1-mediated transcription in the Hedgehog pathway","volume":"18","author":"Mahindroo","year":"2010","journal-title":"Bioorg. Med. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"20600","DOI":"10.1038\/srep20600","article-title":"Nanoquinacrine induced apoptosis in cervical cancer stem cells through the inhibition of hedgehog-GLI1 cascade: Role of GLI-1","volume":"6","author":"Nayak","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1002\/cbic.200700511","article-title":"Naturally occurring small-molecule inhibitors of hedgehog\/GLI-mediated transcription","volume":"9","author":"Hosoya","year":"2008","journal-title":"ChemBioChem"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2551","DOI":"10.1021\/acschembio.8b00492","article-title":"GLI1 Inhibitors Identified by Target Protein Oriented Natural Products Isolation (TPO-NAPI) with Hedgehog Inhibition","volume":"13","author":"Arai","year":"2018","journal-title":"ACS Chem. Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.canlet.2018.02.005","article-title":"Cynanbungeigenin C and D, a pair of novel epimers from Cynanchum bungei, suppress hedgehog pathway-dependent medulloblastoma by blocking signaling at the level of Gli","volume":"420","author":"Li","year":"2018","journal-title":"Cancer Lett."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"13432","DOI":"10.1073\/pnas.1006822107","article-title":"Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector","volume":"107","author":"Kim","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1046\/j.1523-1747.2000.00951.x","article-title":"Regular articles: Conditional disruption of hedgehog signaling pathway defines its critical role in hair development and regeneration","volume":"114","author":"Wang","year":"2000","journal-title":"J. Investig. Dermatol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"4405","DOI":"10.1242\/jcs.112.23.4405","article-title":"Functional antagonists of sonic hedgehog reveal the importance of the N terminus for activity","volume":"112","author":"Williams","year":"1999","journal-title":"J. Cell Sci."},{"key":"ref_64","first-page":"3231","article-title":"Establishment and characterization of a cloned line of C3H mouse embryo cells sensitive to postconfluence inhibition of division","volume":"33","author":"Reznikoff","year":"1973","journal-title":"Cancer Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1006\/bbrc.1997.7156","article-title":"Induction of Osteogenic Differentiation by Hedgehog Proteins","volume":"237","author":"Nakamura","year":"1997","journal-title":"Biochem. Biophys. Res. Comm."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/978-1-60327-258-2_5","article-title":"Enzyme assay design for high-throughput screening","volume":"565","author":"Williams","year":"2009","journal-title":"Meth. Mol. Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1038\/nchembio753","article-title":"Purmorphamine activates the Hedgehog pathway by targeting Smoothened","volume":"2","author":"Sinha","year":"2006","journal-title":"Nat. Chem. Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1016\/j.chembiol.2004.06.010","article-title":"Purmorphamine induces osteogenesis by activation of the hedgehog signaling pathway","volume":"11","author":"Wu","year":"2004","journal-title":"Chem. Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1038\/35023008","article-title":"Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine","volume":"406","author":"Taipale","year":"2000","journal-title":"Nature"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1177\/1087057108318428","article-title":"Application of a high-content multiparameter cytotoxicity assay to prioritize compounds based on toxicity potential in humans","volume":"13","author":"Abraham","year":"2008","journal-title":"SLAS Discov."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1186\/s13046-016-0463-3","article-title":"GANT61, a GLI inhibitor, sensitizes glioma cells to the temozolomide treatment","volume":"35","author":"Li","year":"2016","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"27000","DOI":"10.18632\/oncotarget.25467","article-title":"Investigating the role of Hedgehog\/GLI1 signaling in glioblastoma cell response to temozolomide","volume":"9","author":"Melamed","year":"2018","journal-title":"Oncotarget"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Volnitskiy, A., Shtam, T., Burdakov, V., Kovalev, R., Konev, A., and Filatov, M. (2019). Abnormal activity of transcription factors gli in high-grade gliomas. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0211980"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1158\/1078-0432.CCR-13-2195","article-title":"Hedgehog\u2013GLI signaling inhibition suppresses tumor growth in squamous lung cancer","volume":"20","author":"Huang","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1126\/science.8378770","article-title":"Crystal structure of a five-finger GLI-DNA complex: New perspectives on zinc fingers","volume":"261","author":"Pavletich","year":"1993","journal-title":"Science"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1006\/jmbi.2000.4301","article-title":"Hydrogen bonds with \u03c0-acceptors in proteins: Frequencies and role in stabilizing local 3D structures","volume":"305","author":"Steiner","year":"2001","journal-title":"J. Mol. Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"9250","DOI":"10.18632\/oncotarget.7062","article-title":"In vitro and in vivo inhibition of breast cancer cell growth by targeting the Hedgehog\/GLI pathway with SMO (GDC-0449) or GLI (GANT-61) inhibitors","volume":"7","author":"Benvenuto","year":"2016","journal-title":"Oncotarget"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"4885","DOI":"10.1038\/onc.2010.243","article-title":"Inhibition of GLI, but not Smoothened, induces apoptosis in chronic lymphocytic leukemia cells","volume":"29","author":"Desch","year":"2010","journal-title":"Oncogene"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"5904","DOI":"10.1158\/0008-5472.CAN-10-4173","article-title":"Blocking Hedgehog survival signaling at the level of the GLI genes induces DNA damage and extensive cell death in human colon carcinoma cells","volume":"71","author":"Mazumdar","year":"2011","journal-title":"Cancer Res."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Curran, T. (2018). Reproducibility of academic preclinical translational research: Lessons from the development of Hedgehog pathway inhibitors to treat cancer. Open Biol., 8.","DOI":"10.1098\/rsob.180098"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Bacelar Sacramento de Ara\u00fajo, T., de Oliveira Siquara da Rocha, L., Torres Andion Vidal, M., Cerqueira Coelho, P.L., Galv\u00e3o dos Reis, M., Solano de Freitas Souza, B., Botelho Pereira Soares, M., Almeida Pereira, T., Della Coletta, R., and Pereira Bezerra, D. (2020). GANT61 Reduces Hedgehog Molecule (GLI1) Expression and Promotes Apoptosis in Metastatic Oral Squamous Cell Carcinoma Cells. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176076"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.omto.2021.01.004","article-title":"Structure-based virtual screening identifies an 8-hydroxyquinoline as a small molecule GLI1 inhibitor","volume":"20","author":"Dash","year":"2021","journal-title":"Mol. Ther. Oncolytics"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Li, X., Sun, R., Wu, H., Zheng, C., and Long, Y.-Q. (2023). Targeting the Hedgehog pathway with novel Gli1 hydrophobic tagging degraders. Bioorg. Chem., 138.","DOI":"10.1016\/j.bioorg.2023.106649"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.addr.2016.05.007","article-title":"BDDCS, the Rule of 5 and drugability","volume":"101","author":"Benet","year":"2016","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(96)00423-1","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"23","author":"Lipinski","year":"1997","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/j.ejmech.2018.07.017","article-title":"Synergistic inhibition of the Hedgehog pathway by newly designed Smo and Gli antagonists bearing the isoflavone scaffold","volume":"156","author":"Berardozzi","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Falsini, A., Giuntini, G., Mori, M., Ghirga, F., Quaglio, D., Cucinotta, A., Coppola, F., Filippi, I., Naldini, A., and Botta, B. (2024). Hedgehog Pathway Inhibition by Novel Small Molecules Impairs Melanoma Cell Migration and Invasion under Hypoxia. Pharmaceuticals, 17.","DOI":"10.3390\/ph17020227"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1080\/14728222.2020.1823967","article-title":"The SHH\/GLI signaling pathway: A therapeutic target for medulloblastoma","volume":"24","author":"Ghirga","year":"2020","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Zhang, R., Ma, J., Avery, J.T., Sambandam, V., Nguyen, T.H., Xu, B., Suto, M.J., and Boohaker, R.J. (2020). GLI1 Inhibitor SRI-38832 attenuates chemotherapeutic resistance by downregulating NBS1 transcription in BRAFV600E colorectal cancer. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.00241"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1021\/acsmedchemlett.9b00639","article-title":"Pharmacophore-Based Virtual Screening for Identification of Negative Modulators of GLI1 as Potential Anticancer Agents","volume":"11","author":"Manetti","year":"2020","journal-title":"Med. Chem. Lett."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1021\/acsmedchemlett.2c00249","article-title":"Quinolines and Oxazino-quinoline Derivatives as Small Molecule GLI1 Inhibitors Identified by Virtual Screening","volume":"13","author":"Manetti","year":"2022","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"106858","DOI":"10.1016\/j.phrs.2023.106858","article-title":"Targeting GLI1 and GLI2 with small molecule inhibitors to suppress GLI-dependent transcription and tumor growth","volume":"195","author":"Maresca","year":"2023","journal-title":"Pharmacol. Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"3530","DOI":"10.1038\/s41598-024-53517-y","article-title":"Synthesis and molecular docking simulations of novel azepines based on quinazolinone moiety as prospective antimicrobial and antitumor hedgehog signaling inhibitors","volume":"14","author":"Noser","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"14071","DOI":"10.1073\/pnas.182542899","article-title":"Small molecule modulation of Smoothened activity","volume":"99","author":"Chen","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Frank-Kamenetsky, M., Zhang, X.M., Bottega, S., Guicherit, O., Wichterle, H., Dudek, H., Bumcrot, D., Wang, F.Y., Jones, S., and Shulok, J. (2002). Small-molecule modulators of Hedgehog signaling: Identification and characterization of Smoothened agonists and antagonists. J. Biol., 1.","DOI":"10.1186\/1475-4924-1-10"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1177\/1087057110389323","article-title":"A Fluorescence-Based Alkaline Phosphatase\u2013Coupled Polymerase Assay for Identification of Inhibitors of Dengue Virus RNA-Dependent RNA Polymerase","volume":"16","author":"Niyomrattanakit","year":"2011","journal-title":"J. Biomol. Screen."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.abb.2014.12.014","article-title":"Design and characterization of a photo-activatable hedgehog probe that mimics the natural lipidated form","volume":"567","author":"House","year":"2015","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"105821","DOI":"10.1016\/j.ejps.2021.105821","article-title":"Identification of harmine and \u03b2-carboline analogs from a high-throughput screen of an approved drug collection; profiling as differential inhibitors of DYRK1A and monoamine oxidase A and for in vitro and in vivo anti-cancer studies","volume":"162","author":"Tarpley","year":"2021","journal-title":"Eur. J. Pharm. Sci."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/13\/3095\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:07:22Z","timestamp":1760108842000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/13\/3095"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,28]]},"references-count":98,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["molecules29133095"],"URL":"https:\/\/doi.org\/10.3390\/molecules29133095","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,28]]}}}