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Signal peptide-CUB-EGF-like repeat-containing protein 1-promoted FLT3 signaling is critical for the initiation and maintenance of MLL-rearranged acute leukemia

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Haematologica 2023年第5期108卷 1284-1299页

作者： Binay K Sahoo Yuh-Charn Lin Cheng-Fen Tu Chien-Chin Lin Wei-Ju Liao Fu-An Li Ling-Hui Li Kurt Yun Mou Steve R Roffler Shu-Ping Wang Chi-Tai Yeh Chi-Yuan Yao Hsin-An Hou Wen-Chien Chou Hwei-Fang Tien Ruey-Bing Yang Taiwan International Graduate Program in Molecular Medicine National Yang Ming Chiao Tung University and Academia Sinica Taipei Taiwan Institute of Biomedical Sciences Academia Sinica Taipei. Institute of Biomedical Sciences Academia Sinica Taipei Taiwan Department of Physiology School of Medicine College of Medicine Taipei Medical University Taipei. Institute of Biomedical Sciences Academia Sinica Taipei. Department of Laboratory Medicine Division of Hematology and Department of Internal Medicine National Taiwan University Taipei. Department of Medical Research and Education Taipei Medical University Shuang Ho Hospital New Taipei City. Division of Hematology and Department of Internal Medicine Institute of Biomedical Sciences Academia Sinica Taipei Taiwan Biomedical Translation Research Center Academia Sinica Taipei Taiwan Ph.D. Program in Drug Discovery and Development Industry College of Pharmacy Taipei Medical University Taipei. rbyang@ibms.sinica.edu.tw.

A hallmark of mixed lineage leukemia gene-rearranged (MLL-r) acute myeloid leukemia that offers an opportunity for targeted therapy is addiction to protein tyrosine kinase signaling. One such signal is the receptor tyrosine kinase Fms-like receptor tyrosine kinase 3 (FLT3) upregulated by cooperation of the transcription factors homeobox A9 (HOXA9) and Meis homeobox 1 (MEIS1). Signal peptide-CUB-EGF-like repeat-containing protein (SCUBE) family proteins have previously been shown to act as a co-receptor for augmenting signaling activity of a receptor tyrosine kinase (e.g., vascular endothelial growth factor receptor). However, whether SCUBE1 is involved in the pathological activation of FLT3 during MLL-r leukemogenesis remains unknown. Here we first show that SCUBE1 is a direct target of HOXA9/MEIS1 that is highly expressed on the MLL-r cell surface and predicts poor prognosis in de novo acute myeloid leukemia. We further demonstrate, by using a conditional knockout mouse model, that Scube1 is required for both the initiation and maintenance of MLL-AF9-induced leukemogenesis in vivo. Further proteomic, molecular and biochemical analyses revealed that the membrane-tethered SCUBE1 binds to the FLT3 ligand and the extracellular ligand-binding domains of FLT3, thus facilitating activation of the signal axis FLT3-LYN (a non-receptor tyrosine kinase) to initiate leukemic growth and survival signals. Importantly, targeting surface SCUBE1 by an anti-SCUBE1 monomethyl auristatin E antibody-drug conjugate led to significantly decreased cell viability specifically in MLL-r leukemia. Our study indicates a novel function of SCUBE1 in leukemia and unravels the molecular mechanism of SCUBE1 in MLL-r acute myeloid leukemia. Thus, SCUBE1 is a potential therapeutic target for treating leukemia caused by MLL rearrangements.

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A new capnellene skeleton from the octocoral Capnella imbricata (Quoy & Gaimard, 1833)

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Journal of Molecular Structure 2023年 1271卷

作者： Wu, I-Ting Fan, Yu-Chen Lin, Guan-Zhou Wang, Yi-Lin Hwang, Tsong-Long Lai, Kuei-Hung Chung, Hsu-Ming Department of Applied Chemistry National Pingtung University Pingtung900391 Taiwan Graduate Institute of Biomedical Sciences Graduate Institute of Natural Products College of Medicine Chang Gung University Taoyuan33305 Taiwan Research Center for Chinese Herbal Medicine Graduate Institute of Healthy Industry Technology College of Human Ecology Chang Gung University of Science and Technology Taoyuan33305 Taiwan Department of Chemical Engineering Ming Chi University of Technology New Taipei City243303 Taiwan Department of Anesthesiology Chang Gung Memorial Hospital Taoyuan333 Taiwan PhD Program in Clinical Drug Development of Herbal Medicine College of Pharmacy Taipei Medical University Taipei11031 Taiwan Graduate Institute of Pharmacognosy College of Pharmacy Taipei Medical University Taipei11031 Taiwan Traditional Herbal Medicine Research Center Taipei Medical University Hospital Taipei11031 Taiwan

Chemical investigations on the ethyl acetate extract of the octocoral Capnella imbricata collected from the waters of Taiwan, which led to the isolation of three capnellenes (1–3), including one new metabolite, 9(12)-capnellene-8β,10α,15-triol (1), along with two known metabolites, 9(12)-capnellene-5α,8β,10α-triol (2), and 9(12)-capnellene-8β,10α-diol (3). The structures of the isolated metabolites were elucidated through extensive spectroscopic analyses, while the relative stereochemistry of 3 was confirmed by a single-crystal X-ray diffraction analysis for the first time in this study. Compounds 1–3 were evaluated in terms of their anti-inflammatory activity by examining their inhibitory effects on the generation of superoxide anions and the release of elastase by human neutrophils. © 2022 Elsevier B.V.

关键词： Metabolites

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Citrus fruits, vitamin D, and the RNA virus: A correlation and meta-analysis study in Taiwan and the USA

Food Chemistry Advances

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Food Chemistry Advances 2023年 2卷

作者： Peer, Gajala Deethamvali Ghouse Leal, Elcio Raj, V. Samuel Chang, Chung-Ming Pandey, Ramendra Pati Centre for Drug Design Discovery and Development (C4D) SRM University Delhi-NCR Rajiv Gandhi Education City Haryana Sonepat 131 029 India Department of Biotechnology SRM University Delhi-NCR Rajiv Gandhi Education City Haryana Sonepat 131 029 India Laboratório de Diversidade Viral Instituto de Ciências Biológicas Universidade Federal do Pará Pará Belem 66075-000 Brazil Master & Ph.D. program in Biotechnology Industry Chang Gung University No.259 Wenhua 1st Rd. Guishan Dist. Taoyuan City 33302 Taiwan

Background: The main threat to human health is infectious disease. For the treatment of infections with RNA viruses, there are hardly any antiviral drugs in the market. This is especially concerning because RNA viruses continue to generate the majority of emerging and highly pathogenic viruses, and this trend is expected to continue. The use of phytochemicals in alternative therapies for viral infections is essential. Bioactive compounds of citrus are widely employed to treat a wide range of viral diseases, and calciferol (vitamin D) has been shown to have virucidal effects. According to various researchers from around the world such bioactive chemicals from citrus, along with calciferol, have the potential to have both an inhibitory and a complementary therapeutic effect against RNA viruses. Scope and approach: The purpose of this research is to find the therapeutic effects of vitamin D and citrus fruit to minimize RNA virus virulence by comparing the data and analyzing and by reviewing it and the data collected from the research/ review papers of Taiwan and the United States. Utilizing specified keywords and logical expressions, intensive online searches of pertinent open-access literature found in high-quality and dependable databases served as the foundation for the layout of this review study. Mostly this review is focused on the data of citrus fruit and vitamin d against RNA virus and compared the data from each country. Conclusion: The data information that is available in this paper suggests that consuming enough vitamin D and secondary metabolites from citrus fruits are linked to a much lower risk of contracting RNA virus infections. © 2023 The Author(s)

关键词： Citrus Taiwan United States Viral diseases Vitamin D

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A Novel Sterol from the Formosan Soft Coral Lobophytum Durum

SSRN

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SSRN 2023年

作者： Hung, Chia-Ling Huang, Li-Chieh Shih, Kun-Yauh Lai, Kuei-Hung Peng, Bo-Rong Hwang, Tsong-Long Li, Chia-Ying Chung, Hsu-Ming Department of Applied Chemistry National Pingtung University Pingtung900391 Taiwan Graduate Institute of Pharmacognosy College of Pharmacy Taipei Medical University Taipei11031 Taiwan PhD Program in Clinical Drug Development of Herbal Medicine College of Pharmacy Taipei Medical University Taipei11031 Taiwan Traditional Herbal Medicine Research Center Taipei Medical University Hospital Taipei11031 Taiwan Graduate Institute of Natural Products College of Medicine Chang Gung University Taoyuan333323 Taiwan Research Center for Chinese Herbal Medicine Graduate Institute of Healthy Industry Technology College of Human Ecology Chang Gung University of Science and Technology Taoyuan333324 Taiwan Department of Chemical Engineering Ming Chi University of Technology New Taipei City243303 Taiwan Department of Anesthesiology Chang Gung Memorial Hospital Taoyuan333423 Taiwan

Chromatographic investigation on the ethyl acetate extract of the soft coral Lobophytum durum collected from the waters of Guishan Island in northeast Taiwan resulted in the isolation of three sterols 1–3, including one novel sterol, 3β-hydroxy-25-methylene-5-cholesten-7-one (1), and two previously reported sterols, 7-oxogorgosterol (2), and (24S)-ergostane-3β,5α,6β,25-tetraol 25-monoacetate (3). The structures of sterols 1–3 were determined by extensive spectroscopic data analysis and by comparison with those previously reported in the literature. Additionally, the absolute configuration of sterol 3 was identified by a single-crystal X-ray diffraction analysis for the first time in this study. The anti-inflammatory activities of sterols 1–3 were evaluated by examining their inhibitory effects on the generation of superoxide anions and the release of elastase by human neutrophils. © 2023, The Authors. All rights reserved.

关键词： Spectroscopic analysis

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Synthesis and biological evaluation of C-4 substituted phenoxazine-bearing hydroxamic acids with potent class II histone deacetylase inhibitory activities

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Journal of enzyme inhibition and medicinal chemistry 2023年第1期38卷 2212326页

作者： Jung-Chun Chu Hui-Ju Tseng Sung-Bau Lee Kai-Cheng Hsu Ling-Wei Hsin Ru-Hao Liang Tony Eight Lin Nain-Chu Gao Liang-Chieh Chen Wan-Hsun Lu Andrew H-J Wang Wei-Jan Huang Ph.D. Program in Drug Discovery and Development Industry College of Pharmacy Taipei Medical University Taipei Taiwan. School of Pharmacy Taipei Medical University Taipei Taiwan. Department of Pharmacology and Pharmaceutical Sciences School of Pharmacy University of Southern California Los Angeles California United States. Graduate Institute of Cancer Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei Taiwan. Ph.D. Program for Cancer Molecular Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei Taiwan. TMU Research Center for Drug Discovery Taipei Medical University Taipei Taiwan. School of Pharmacy College of Medicine National Taiwan University Taipei Taiwan. Graduate Institute of Pharmacognosy College of Pharmacy Taipei Medical University Taipei Taiwan. The Ph.D. Program for Translational Medicine College of Medical Science and Technology Taipei Medical University Taipei Taiwan.

Class II histone deacetylases (HDACs) are considered as potential targets to treat Alzheimer's disease (AD). Previously, C-3 substituted phenothiazine-containing compounds with class II HDAC-inhibiting activities was found to promote neurite outgrowth. This study replaced phenothiazine moiety with phenoxazine that contains many C-3 and C-4 substituents. Some resulting compounds bearing the C-4 substituent on a phenoxazine ring displayed potent class II HDAC inhibitory activities. Structure-activity relationship (SAR) of these compounds that inhibited HDAC isoenzymes was disclosed. Molecular modelling analysis demonstrates that the potent activities of C-4 substituted compounds probably arise from π-π stacked interactions between these compounds and class IIa HDAC enzymes. One of these, compound exhibited the most potent class II HDAC inhibition (IC= 3-870 nM). Notably, it protected neuron cells from HO-induced neuron damage at sub-μM concentrations, but with no significant cytotoxicity. These findings show that compound is a lead compound for further development of anti-neurodegenerative agents.

关键词： Histone deacetylase (HDAC) neuron cells phenoxazine structure-activity relationship (SAR)

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discovery of Novel Zoanthamine-Type Alkaloids Derived from Cultured Zoanthus Kuroshio with Prominent Therapeutic Potential Against Osteoporosis

SSRN

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SSRN 2025年

作者： Pham, Ngoc-Thac Peng, Bo-Rong Le, Huong-Giang Chen, Yun-Shiuan Huynh, Thanh Hao Chen, Lo-Yun Nguyen, Le Anh Tuan Nguyen, Dang T. Su, Jui-Hsin El-Shazly, Mohamed Lee, Mei-Hsien Lai, Kuei-Hung PhD Program in Clinical Drug Development of Herbal Medicine College of Pharmacy Taipei Medical University Taipei110301 Taiwan Graduate Institute of Pharmacognosy College of Pharmacy Taipei Medical University Taipei110301 Taiwan Graduate Institute of Healthy Industry Technology Research Center for Chinese Herbal Medicine College of Human Ecology Chang Gung University of Science and Technology Taoyuan333324 Taiwan Faculty of Pharmacy Lac Hong University Dongnai Bien Hoa Viet Nam Faculty of Applied Sciences Ton Duc Thang University Ho Chi Minh City Viet Nam National Museum of Marine Biology and Aquarium Pingtung944401 Taiwan Department of Marine Biotechnology and Resources National Sun Yat-sen University Kaohsiung804201 Taiwan Department of Pharmacognosy Faculty of Pharmacy Ain-Shams University Organization of African Unity Street Abassia Cairo11566 Egypt Center for Reproductive Medicine and Sciences Taipei Medical University Hospital Taipei110301 Taiwan Traditional Herbal Medicine Research Center Taipei Medical University Hospital Taipei110301 Taiwan

Marine invertebrates are well-established as prolific sources of secondary metabolites, renowned for their remarkable chemical diversity and extensive spectrum of biological activities. Among these, Zoanthus Kuroshio (ZK) has gained significant attention due to its abundant chemical constituents, particularly alkaloids, which exhibit promising bioactivities against osteoporosis. To investigate its therapeutic potential, the extracts of cultured ZK exhibited significant anti-osteoporotic activity in vitro with MG-63 cells, leading to the integration of Global Natural Products Social Molecular Networking (GNPS) to identify fractions containing the highest amounts of alkaloids. Subsequent isolation efforts resulted in the discovery of five novel zoanthamine-type alkaloids: norzoabenzaldehyde (1), norzoazepanol (2), 11-keto-3-acetoxynorzoanthamine (3), 11-hydroxynorzoanthamide B (4), and 11-hydroxyzoanthamide B (5), alongside four previously identified compounds, including norzoanthaminone (6), 3-acetoxynorzoanthamine (7), 3-acetoxyzoanthamine (8), and 3-hydroxynorzoanthamine (9). Structural elucidation of compounds 1, 3, 4, and 5 was achieved using comprehensive spectroscopic analyses, whereas compound 2 required advanced techniques, including time-dependent density functional theory nuclear magnetic resonance (TDDFT-NMR) calculations and comparative analysis of theoretical and experimental electronic circular dichroism (ECD) data, to ascertain its absolute configuration. Bioassays evaluating alkaline phosphatase activity and mineralization demonstrated that compound 9 exhibited significant activity, with an IC50 value of 20 µM. The mechanism by which this compound operates was elucidated through network pharmacology, molecular docking and dynamics simulations, further confirming the stability of interactions between compound 9 and key protein targets, thereby emphasizing its potential as a promising lead compound for osteoporosis therapeutics. © 2025, The Authors. All

关键词： Spectroscopic analysis

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Agar-altered foaming bacterial cellulose with carvacrol for active food packaging applications

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Food Packaging and Shelf Life 2024年 42卷

作者： Kusuma, Anita Chandra Chou, Yu-Chieh Hsieh, Chen-Che Santoso, Shella Permatasari Go, Alchris Woo Lin, Hong-Ting Victor Hsiao, I.-Lun Lin, Shin-Ping Master Program in Food Safety Taipei Medical University 250 Wu-Hsing Street Taipei 11031 Taiwan Ph.D. Program in Drug Discovery and Development Industry Taipei Medical University 250 Wu-Hsing Street Taipei 11031 Taiwan Institute of Biotechnology National Taiwan University 1 Roosevelt Rd. Section 4 Taipei 10617 Taiwan Department of Chemical Engineering Widya Mandala Surabaya Catholic University Kalijudan 37 Surabaya 60114 Indonesia Department of Chemical Engineering National Taiwan University of Science and Technology 43 Keelung Road Section 4 Taipei 10607 Taiwan Department of Food Science National Taiwan Ocean University No. 2 Pei-Ning Road Keelung 20224 Taiwan School of Food Safety Taipei Medical University 250 Wu-Hsing Street Taipei 11031 Taiwan TMU Research Center for Digestive Medicine Taipei Medical University 250 Wu-Hsing Street Taipei 11031 Taiwan Research Center of Biomedical Device Taipei Medical University 250 Wu-Hsing Street Taipei 11031 Taiwan

Bacterial cellulose (BC) is a biodegradable nanoscale film produced by microorganisms, which possesses great mechanical properties and biocompatibility. In this study, we produced foaming BC (FBC) utilizing foam medium with different concentrations of agar. In addition, carvacrol was loaded into the agar/FBC to establish active packaging material. Evaluation by characterization tests indicated that agar/FBC provided lower crystallinity (59.8%∼71.4%) and a high swelling ability (94.7%∼97.9%) compared to BC (92.2% and 96.1%). The 1.5% agar/FBC with carvacrol group exhibited the significantly highest antimicrobial properties against Escherichia coli and Staphylococcus aureus. Moreover, release measurements showed that greater agar addition contributed to higher protein and carvacrol release extents out of the film. Finally, a sea bass packaging test indicated that carvacrol with 1.5% agar/FBC presented a higher antimicrobial ability against Shewanella putrefaciens, great inhibition of lipid oxidation (67.5%), and a slower spoilage degree (49.8%) which suggested that agar/FBC with carvacrol has potential for active food packaging. © 2024 Elsevier Ltd

关键词： Agar Bacterial cellulose Carvacrol Foaming bacterial cellulose Food packaging Sea bass

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Improvement of extracellular polysaccharides production from Cordyceps militaris immobilized alginate beads in repeated-batch fermentation

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LWT 2024年 193卷

作者： Hou, Shi-Jing Cheng, Kuan-Chen Lin, Shyh-Hsiang Hsiao, I-Lun Santoso, Shella Permatasari Singajaya, Stephanie Chou, Yu-Chieh Lin, Shin-Ping Master Program in Food Safety Taipei Medical University 250 Wu-Hsing Street Taipei11031 Taiwan Institute of Biotechnology National Taiwan University 1 Roosevelt Rd. Sec. 4 Taipei10617 Taiwan Graduate Institute of Food Science and Technology National Taiwan University 1 Roosevelt Rd. Sec. 4 Taipei10617 Taiwan Department of Medical Research China Medical University Hospital China Medical University 91 Hsueh-Shih Rd. Taichung40402 Taiwan Department of Optometry Asia University 500 Lioufeng Rd. Wufeng Taichung41354 Taiwan School of Nutrition and Health Sciences Taipei Medical University 250 Wu-Hsing Street Taipei11031 Taiwan School of Food Safety Taipei Medical University 250 Wu-Hsing Street Taipei11031 Taiwan Department of Chemical Engineering Widya Mandala Surabaya Catholic University Kalijudan 37 East Java Surabaya60114 Indonesia Collaborative Research Center for Sustainable and Zero Waste Industries Kalijudan 37 East Java Surabaya60114 Indonesia Ph.D. Program in Drug Discovery and Development Industry Taipei Medical University 250 Wu-Hsing Street Taipei11031 Taiwan Research Center of Biomedical Device Taipei Medical University 250 Wu-Hsing Street Taipei11031 Taiwan TMU Research Center for Digestive Medicine Taipei Medical University 250 Wu-Hsing Street Taipei11031 Taiwan

Cordyceps militaris (C. militaris) is a unique medicinal fungus of the genus Cordyceps. It has high economic value due to various biological functions from the extracellular polysaccharides (EPSs) it produces. The aim of this study was to establish a mycelium-immobilization system for EPS production in a bubble column system. First, EPS production was optimized by 90.2% (from 0.72 to 1.37 g/L) using response surface methodology under an alginate-immobilized mycelium system with 6 days of cultivation. The highest EPS production was obtained (5.3 g/L) in a flask system through elongation to 15 days of cultivation. EPS production subsequently further increased to 10.42 g/L utilizing a bubble column reactor. Furthermore, the system can be reused for at least three rounds. In the EPS characteristics analysis, the produced EPSs were mainly composed of glucose and galactose. They presented strong antibacterial activity against Staphylococcus aureus. In terms of antioxidant activity, respective the EPS concentration that caused 50% scavenging of DPPH and ABTS free radicals values (IC50) were 4.65 and 7.92 mg/mL. In summary, these findings should be helpful for establishing a suitable industrial fermentation system for C. militaris and can be studied in the food and medical industries in future work. © 2024 The Authors

关键词： Mycelium

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Air pollution and its impacts on health: Focus on microplastics and nanoplastics

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Ecotoxicology and Environmental Safety 2025年 299卷 118402页

作者： Wang, Yung-Li Lin, Yen-Chung Liu, Wen-Chih Lee, Yu-Hsuan Chiu, Hui-Wen Graduate Institute of Clinical Medicine College of Medicine Taipei Medical University Taipei Taiwan Division of Nephrology Department of Internal Medicine Taipei Medical University Hospital Taipei Taiwan Division of Nephrology Department of Internal Medicine School of Medicine College of Medicine Taipei Medical University Taipei Taiwan TMU Research Center of Urology and Kidney Taipei Medical University Taipei Taiwan Section of Nephrology Department of Medicine Antai Medical Care Corporation Antai Tian-Sheng Memorial Hospital Pingtung Taiwan Department of Nursing Meiho University Pingtung Taiwan Department of Biology and Anatomy National Defense Medical Center Taipei Taiwan Department of Cosmeceutics China Medical University Taichung Taiwan Institute of Environmental and Occupational Health Sciences School of Medicine National Yang Ming Chiao Tung University Taipei Taiwan Department of Medical Research Shuang Ho Hospital Taipei Medical University New Taipei City Taiwan Ph.D. Program in Drug Discovery and Development Industry College of Pharmacy Taipei Medical University Taipei Taiwan

Air pollution represents a significant public health concern, contributing to approximately 6.7 million premature deaths annually. Among the various pollutants, particulate matter (PM)_2.5, emitted from fossil fuel combustion, poses a significant health risk. It induces oxidative stress and increases respiratory and cardiovascular disease risk. Recently, particulate plastics, classified as microplastics (MPs) (less than 5 mm) or nanoplastics (NPs) (less than 1 μm), have been identified as environmental contaminants. It has been demonstrated that plastic particles, including MPs and NPs, can gain access to the human body via inhalation, ingestion, and dermal contact, resulting in various adverse health effects, such as inflammation and oxidative stress. Particulate plastics have been identified in human biological samples, including blood, saphenous vein tissues and lung tissues. Moreover, their presence in PM_2.5, particularly in urban settings, exacerbates the health risks associated with air pollution. This review addresses the sources, detection, health effects, and mitigation strategies for particulate plastics in the atmosphere. Additionally, the study discusses the biological degradation of particulate plastics by microorganisms and the potential of advanced oxidation processes for their removal. These comprehensive approaches could reduce the environment and human health from the adverse effects of airborne particulate plastics. © 2025 The Authors

关键词： Air pollution Health risks Microplastics Nanoplastics Oxidative stress PM2.5

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Computer-aided drug discovery of a dual-target inhibitor for ovarian cancer: therapeutic intervention targeting CDK1/TTK signaling pathway and structural insights in the NCI-60

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Computers in biology and medicine 2025年 193卷 110445页

作者： Sung-Ling Tang Maryam Rachmawati Sumitra Yu-Cheng Kuo Han-Lin Hsu Muhamad Ansar Sheng-Liang Huang Shih-Yu Lee Hong-Jaan Wang Bashir Lawal Alexander T H Wu Lung-Ching Chen Hsu-Shan Huang School of Pharmacy National Defense Medical Center Taipei 11490 Taiwan. PhD Program for Cancer Molecular Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei 11031 Taiwan Graduate Institute of Cancer Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei 11031 Taiwan. Department of Pharmacology School of Medicine College of Medicine Taipei Medical University Taipei 11031 Taiwan School of Post-Baccalaureate Chinese Medicine College of Chinese Medicine China Medical University Taichung 40604 Taiwan. Graduate Institute of Clinical Medicine Taipei Medical University Taipei 11031 Taiwan Division of Pulmonary Medicine Department of Internal Medicine Wanfang Hospital Taipei Medical University Taipei 11031 Taiwan. Ph.D. Program in the Clinical Drug Development of Herbal Medicine Taipei Medical University Taipei 110301 Taiwan. Graduate Institute of Aerospace and Undersea Medicine National Defense Medical Center Taipei 11490 Taiwan. UPMC Hillman Cancer Center University of Pittsburgh Pittsburgh PA USA. Ph.D. Program of Translational Medicine College of Science and Technology Taipei Medical University Taipei 11031 Taiwan. Division of Cardiology Department of Internal Medicine Shin Kong Wu Ho-Su Memorial Hospital Taipei 11101 Taiwan. School of Pharmacy National Defense Medical Center Taipei 11490 Taiwan Graduate Institute of Cancer Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei 11031 Taiwan Ph.D. Program in Biotechnology Research and Development College of Pharmacy Taipei Medical University Taipei 11031 Taiwan. Electronic address: huanghs99@tmu.edu.tw.

Ovarian cancer remains the third most prevalent and deadliest gynecologic malignancy worldwide, with most patients eventually developing resistance to platinum-based chemotherapy. This highlights a critical unmet need for innovative multitargeted therapies to address current treatment challenges. In this study, we identified 35 differentially expressed genes (DEGs) through integrated analysis of four GEO ovarian cancer datasets, with validation using TCGA data. Gene Ontology (GO) and KEGG enrichment analyses highlighted key tumor-associated pathways, and protein-protein interaction (PPI) network modeling prioritized CDK1 and TTK as high-value therapeutic targets. We evaluated the association between molecular genomic features and drug responses across the NCI-60 ovarian cancer cell line panel (IGROV1, OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, NCI/ADR-RES, and SK-OV-3), using a series of salicylanilide-derived compounds and four FDA-approved drugs (cabozantinib, paclitaxel, rapamycin, and niclosamide) from the NCI developmental Therapeutics program (DTP). Among these, NSC765690 (MCC22) emerged as the most promising candidate. It demonstrated potent antiproliferative activity, high target selectivity, and strong binding affinity to both CDK1 and TTK. Multi-omics integration, combined with AI-driven network modeling, further elucidated NSC765690's mechanism of action and its relevance to ovarian cancer pathogenesis. Additionally, ADMET and pharmacokinetic profiling confirmed its favorable drug-like properties and low predicted toxicity. Collectively, these findings establish NSC765690 as a potent dual-target inhibitor and exemplify a rational, data-driven drug discovery pipeline for overcoming chemotherapy resistance in ovarian cancer.

关键词： Dual-target small molecule inhibitor Machine learning Molecular docking Molecular dynamics simulations NCI-60 panel Ovarian cancer

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