Consensus Pharmacological Interactions for PLK2 Inhibitor Identification in Colorectal Cancer Treatment

Consensus Pharmacological Interactions for PLK2 Inhibitor Identification in Colorectal Cancer Treatment | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 22 August 2025 V1 Latest version Share on Consensus Pharmacological Interactions for PLK2 Inhibitor Identification in Colorectal Cancer Treatment Authors : Yi-Wen Wu , Chun-Lin Yang , Tony Lin , Yun-Hsuan Yeh , Yu-Ting Fang-Chin , Tzu-Ying Sung , Shih-Chung Yen , Jui-Hua Hsieh , CHENG-CHIH CHUNG , Shiow-Lin Pan 0000-0001-7449-3539 , and Kai-Cheng Hsu [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.175584841.11099249/v1 Published Journal of Chemical Information and Modeling Version of record Peer review timeline 134 views 92 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background and Purpose Polo-like kinase 2 (PLK2) is a critical regulator of cellular stress responses, redox balance, and tumour progression. In colorectal cancer (CRC), elevated PLK2 expression promotes chemoresistance and poor prognosis by modulating signaling pathways involving GSK3β and NRF2, thereby positioning PLK2 as an attractive therapeutic target. Experimental Approach We applied a structure-based drug discovery (SBDD) strategy to construct a consensus virtual screening model that integrates pharmacological interactions from multiple PLK2 crystal structures. Using this model, we screened the ChemDiv compound library to identify candidate inhibitors. Selected compounds were subsequently evaluated through structure–activity relationship (SAR) analysis, enzymatic profiling, and functional assays in colorectal cancer cell lines. Key Results The consensus model enhanced screening performance, increasing ROC-AUC from 0.906 to 0.930, and identified two novel PLK2 inhibitors. Among them, compounds Y207-5465 (IC 50 584.3 nM) and 8012-3246 (IC 50 774.5 nM) exhibited submicromolar inhibition. In vitro analysis, 8012-3246 demonstrated potent cytotoxicity (IC 50 : 7.97 and 17.67 μM) and anti-proliferative activity (GI 50 : 3.28 and 6.62 μM) in HT-29 and HCT-116 CRC cells, with high kinase selectivity. Mechanistic studies revealed that 8012-3246 suppressed GSK3β phosphorylation, disrupting PLK2-mediated redox signaling and cell survival pathways. Conclusion and Implications Consensus pharmacological interaction modelling represents an effective strategy for identifying selective kinase inhibitors. Our findings establish PLK2 inhibition as a promising therapeutic approach in CRC and nominate 8012-3246 as a strong candidate for further preclinical development. Supplementary Material File (figures.pdf) Download 5.25 MB File (manuscript_plk2.docx) Download 10.02 MB File (tables.docx) Download 243.67 KB Information & Authors Information Version history V1 Version 1 22 August 2025 Peer review timeline Published Journal of Chemical Information and Modeling Version of Record 17 Dec 2025 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Affiliations Yi-Wen Wu Taipei Medical University Graduate Institute of Cancer Biology and Drug Discovery View all articles by this author Chun-Lin Yang Taipei Medical University Graduate Institute of Cancer Biology and Drug Discovery View all articles by this author Tony Lin Taipei Medical University Graduate Institute of Cancer Biology and Drug Discovery View all articles by this author Yun-Hsuan Yeh Taipei Medical University Graduate Institute of Cancer Biology and Drug Discovery View all articles by this author Yu-Ting Fang-Chin Taipei Medical University Graduate Institute of Cancer Biology and Drug Discovery View all articles by this author Tzu-Ying Sung Taipei Medical University Graduate Institute of Cancer Biology and Drug Discovery View all articles by this author Shih-Chung Yen The Chinese University of Hong Kong - Shenzhen School of Management and Economics View all articles by this author Jui-Hua Hsieh National Institute of Environmental Health Sciences View all articles by this author CHENG-CHIH CHUNG Taipei Medical University College of Medicine View all articles by this author Shiow-Lin Pan 0000-0001-7449-3539 Taipei Medical University Graduate Institute of Cancer Biology and Drug Discovery View all articles by this author Kai-Cheng Hsu [email protected] Taipei Medical University Graduate Institute of Cancer Biology and Drug Discovery View all articles by this author Metrics & Citations Metrics Article Usage 134 views 92 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Yi-Wen Wu, Chun-Lin Yang, Tony Lin, et al. Consensus Pharmacological Interactions for PLK2 Inhibitor Identification in Colorectal Cancer Treatment. Authorea . 22 August 2025. DOI: https://doi.org/10.22541/au.175584841.11099249/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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