{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T19:54:23Z","timestamp":1790884463587,"version":"4.1.0"},"reference-count":32,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>The PI3K plays a crucial role in cancer progression, and the development of PI3K inhibitors has always been a hot research direction in oncology. Through virtual screening and docking, potential lead compounds were identified. ADMET prediction revealed that KTC101 possesses superior pharmacokinetic profile. Molecular dynamics simulations indicated that compound KTC101 could stably bind to PI3K\u03b4, with a binding free energy of \u2212374.627 kJ\/mol. Analysis of the metabolism of KTC101 revealed that this compound could undergo diverse phase I metabolic reactions catalyzed by hepatic CYP450 enzymes to form highly polar metabolites, indicating its strong metabolic potential and easy metabolic clearance in vivo. Then it was synthesized and evaluated for kinase inhibitory activity and antiproliferative effects in HNSCC cell lines. KTC101 was first reported as a PI3K inhibitor, with IC50 values of 191.23 \u00b1 40.84 nM, 23.30 \u00b1 5.68 nM, and 146.20 \u00b1 21.82 nM for PI3K\u03b1, PI3K\u03b4 and PI3K\u03b3, respectively, and demonstrated dose-dependent inhibition of cancer cell growth in vitro, with IC50 values of 4.1 \u00b1 0.73 \u03bcM for HSC3 cells and 2.2 \u00b1 0.11 \u03bcM for HSC4 cells. It exhibited inhibitory activity against PI3K, showing greater inhibitory potency toward PI3K\u03b4. This study demonstrates the anti-tumor potential of KTC101.<\/jats:p>","DOI":"10.3390\/biology15191742","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:43:24Z","timestamp":1790880204000},"page":"1742","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In Silico Evaluation via Virtual Screening, ADMET Profiling and Molecular Dynamics Simulations: Synthesis and Biological Activity Analysis of a Novel Antitumor PI3K Inhibitor"],"prefix":"10.3390","volume":"15","author":[{"given":"Wenqing","family":"Jia","sequence":"first","affiliation":[{"name":"School of Chemistry and Chemical Engineering, Qilu Normal University, Jinan 250200, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Yukui","family":"Ma","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering, Qilu Normal University, Jinan 250200, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Zhe","family":"Zhang","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1146\/annurev.cellbio.17.1.615","article-title":"Cellular function of phosphoinositide 3-kinases: Implications for development, homeostasis, and cancer","volume":"17","author":"Katso","year":"2001","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1186\/s12943-024-02072-1","article-title":"Targeting PI3K family with small-molecule inhibitors in cancer therapy: Current clinical status and future directions","volume":"23","author":"Li","year":"2024","journal-title":"Mol. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/s41586-023-05972-2","article-title":"A small-molecule PI3K\u03b1 activator for cardioprotection and neuroregeneration","volume":"618","author":"Gong","year":"2023","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"100657","DOI":"10.1016\/j.jbior.2019.100657","article-title":"Class I phosphoinositide 3-kinase (PI3K) regulatory subunits and their roles in signaling and disease","volume":"75","author":"Rathinaswamy","year":"2020","journal-title":"Adv. Biol. Regul."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s12943-024-01978-0","article-title":"A novel pan-PI3K inhibitor KTC1101 synergizes with anti-PD-1 therapy by targeting tumor suppression and immune activation","volume":"23","author":"Peng","year":"2024","journal-title":"Mol. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"8587","DOI":"10.1080\/07391102.2022.2132293","article-title":"Development of PI3K\u03b1 inhibitors for tumor therapy","volume":"41","author":"Jia","year":"2023","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Jia, W. (2026). Targeting PI3K\u03b4 for lymphoma and immune diseases treatment: A review. Mol. Divers., 1\u201329.","DOI":"10.1007\/s11030-026-11536-z"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e003762","DOI":"10.1136\/jitc-2021-003762","article-title":"PI3K\u03b4\/\u03b3 inhibitor BR101801 extrinsically potentiates effector CD8(+) T cell-dependent antitumor immunity and abscopal effect after local irradiation","volume":"10","author":"Yoon","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e514","DOI":"10.1002\/ctm2.514","article-title":"Dual blocking of PI3K and mTOR signaling by DHW-221, a novel benzimidazole derivative, exerts antitumor activity in human non-small cell lung cancer","volume":"11","author":"Qin","year":"2021","journal-title":"Clin. Transl. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1186\/s12943-023-01827-6","article-title":"PI3K\/AKT\/mTOR signaling transduction pathway and targeted therapies in cancer","volume":"22","author":"Glaviano","year":"2023","journal-title":"Mol. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1038\/s41392-022-00945-9","article-title":"MrgprF acts as a tumor suppressor in cutaneous melanoma by restraining PI3K\/Akt signaling","volume":"7","author":"Shen","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1038\/aps.2012.72","article-title":"PI3K and Akt as molecular targets for cancer therapy: Current clinical outcomes","volume":"33","author":"Pal","year":"2012","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Siddika, T., Balasuriya, N., Frederick, M.I., Rozik, P., Heinemann, I.U., and O\u2019Donoghue, P. (2022). Delivery of active AKT1 to human cells. Cells, 11.","DOI":"10.3390\/cells11233834"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/1750-9378-8-49","article-title":"Akt inhibitors: Mechanism of action and implications for anticancer therapeutics","volume":"8","author":"Bhutani","year":"2013","journal-title":"Infect. Agent. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1002\/hep.27396","article-title":"4EBP1\/eIF4E and p70S6K\/RPS6 axes play critical and distinct roles in hepatocarcinogenesis driven by AKT and N-Ras proto-oncogenes in mice","volume":"61","author":"Wang","year":"2015","journal-title":"Hepatology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1007\/s13402-016-0272-x","article-title":"A novel curcumin-like dienone induces apoptosis in triple-negative breast cancer cells","volume":"39","author":"Das","year":"2016","journal-title":"Cell Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Leiphrakpam, P.D., Batra, R., Tenner, L., and Are, C. (2025). Targeting Akt signaling pathway in cancer: Molecular mechanisms and advances in therapeutic interventions. Front. Biosci., 30.","DOI":"10.31083\/FBL39100"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1038\/s43018-021-00218-4","article-title":"The present and future of PI3K inhibitors for cancer therapy","volume":"2","author":"Castel","year":"2021","journal-title":"Nat. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"406","DOI":"10.7555\/JBR.28.20130110","article-title":"Molecular docking studies of anti-cancerous candidates in Hippophae rhamnoides and Hippophae salicifolia","volume":"28","author":"Usha","year":"2014","journal-title":"J. Biomed. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/nchembio.293","article-title":"The p110 delta structure: Mechanisms for selectivity and potency of new PI(3)K inhibitors","volume":"6","author":"Berndt","year":"2010","journal-title":"Nat. Chem. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Jia, W., Li, G., Cheng, X., Zhang, R., and Ma, Y. (2025). In silico discovery of a novel potential allosteric PI3K\u03b1 inhibitor incorporating 2-oxopropyl urea targeting head and neck squamous cell carcinoma. BMC Chem., 19.","DOI":"10.1186\/s13065-025-01420-6"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1038\/s41597-024-03793-0","article-title":"PharmaBench: Enhancing ADMET benchmarks with large language models","volume":"11","author":"Niu","year":"2024","journal-title":"Sci. Data"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"W422","DOI":"10.1093\/nar\/gkae236","article-title":"ADMETlab 3.0: An updated comprehensive online ADMET prediction platform enhanced with broader coverage, improved performance, API functionality and decision support","volume":"52","author":"Fu","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"10204","DOI":"10.1021\/acs.est.5c03906","article-title":"Combined analysis of network toxicology and multiomics revealed the potential mechanism of 6PPDQ-induced hepatotoxicity in mice","volume":"59","author":"Li","year":"2025","journal-title":"Environ. Sci. Technol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Jia, W., Liu, J., Cheng, X., Li, X., and Ma, Y. (2024). In Silico Discovery of a novel PI3K\u03b4 inhibitor incorporating 3,5,7-trihydroxychroman-4-one targeting diffuse large B-cell lymphoma. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252011250"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10185","DOI":"10.1007\/s00210-026-04991-w","article-title":"Synthesis and integrative multimodal evaluation of cholic acid-based hydrazone conjugates: In vitro, in silico, and in vivo studies","volume":"399","author":"Butt","year":"2026","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"bbae166","DOI":"10.1093\/bib\/bbae166","article-title":"RmsdXNA: RMSD prediction of nucleic acid-ligand docking poses using machine-learning method","volume":"25","author":"Tan","year":"2024","journal-title":"Brief. Bioinform."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Jia, W., and Cheng, X. (2025). In silico discovery of a novel potential allosteric PI3K\u03b1 inhibitor incorporating 3-(2-chloro-5-fluorophenyl)isoindolin-1-one to target head and neck squamous cell carcinoma. Biology, 14.","DOI":"10.3390\/biology14070896"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4456","DOI":"10.1021\/acs.jctc.3c01366","article-title":"Exact analytical algorithm for the solvent-accessible surface area and derivatives in implicit solvent molecular simulations on GPUs","volume":"20","author":"Cao","year":"2024","journal-title":"J. Chem. Theory Comput."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Elnageeb, M.E., Elfaki, I., Modawe, G.A., Elfaki, A.O., Alzahrani, O.R., Abuagla, H.A., Alwabsi, H.A., Alalawy, A.I., Ajmal, M.R., and Mohamed, E.I. (2025). Computational prediction of the pathogenic variants of arachidonate 5-lipoxygenase activating protein using Molecular Dynamics simulation. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0329126"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1111\/jop.12248","article-title":"Down-regulation of Akt by methanol extracts of Impatiens balsamina L. promotes apoptosis in human oral squamous cell carcinoma cell lines","volume":"20","author":"Shin","year":"2015","journal-title":"J. Oral Pathol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Xu, H., Luo, X., He, X., Jin, X., Zhang, Y., and Xu, X. (2026). Inhibition of PI3K\/AKT\/mTOR pathway suppresses growth of oral squamous cell carcinoma in 2D and 3D in vitro model and animal model. Genes Genom., 1\u201315.","DOI":"10.1007\/s13258-026-01791-7"}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/19\/1742\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:56:55Z","timestamp":1790881015000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/19\/1742"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,1]]},"references-count":32,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["biology15191742"],"URL":"https:\/\/doi.org\/10.3390\/biology15191742","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,1]]}}}