Research Breakthrough by Sun Yat-sen University Team on the Active Ingredients of Genkwadaphnin in Treating Prostate Cancer with Click Chemistry
Current Status and Research Background of Prostate Cancer Treatment
Prostate cancer, one of the most common malignant tumors in the male urinary system, faces severe treatment challenges. Currently, standard clinical treatment for early-stage prostate cancer is androgen deprivation therapy; however, as treatment progresses, most cases eventually develop into castration-resistant prostate cancer (CRPC). At this stage, cancer cells exhibit resistance to androgen deprivation therapy, significantly reducing the effectiveness of traditional treatment plans.
In clinical treatments for CRPC, first-line drugs such as enzalutamide and abiraterone show some efficacy initially but often lose their effectiveness over long-term use due to acquired resistance mechanisms formed by tumor cells. This therapeutic dilemma highlights the urgency to develop new anti-CRPC drugs that can overcome existing drug resistance.
Discovery and Pharmacological Properties of Genkwadaphnin
Genkwadaphnin is a dibenzodioxole compound with significant medicinal value derived from the flower buds of Daphne genkwa. In the 2020 edition of the Chinese Pharmacopoeia, Daphne genkwa is recorded as a commonly used traditional Chinese medicine known for its diuretic and detoxifying properties. Modern pharmacological studies have revealed various biological activities associated with Genkwadaphnin including notable antiviral effects, immune regulation functions, and antitumor effects.
Professors Yin Sheng and Wang Junjian's team at Sun Yat-sen University's School of Pharmacy discovered a small molecule classified as DD1 during systematic screening within a library containing Euphorbiaceae-derived diterpenes. This compound exhibited strong inhibitory effects against CRPC both in vitro and in vivo experiments. This important finding was published in September 2022 in the Journal of American Chemical Society (impact factor 16.383), titled "Discovery of an Efficient Diterpene Reveals Nuclear Transport Protein Importin-β1 as a Drug Vulnerability Target for Castration-Resistant Prostate Cancer".
Screening Drugs Against CRPC and Efficacy Validation Studies
The research team established a natural product library consisting of 255 compounds covering 16 classes based on Euphorbiaceae diterpenes' structural frameworks. Through systematic growth inhibition experiments using CRPC cell line C4-2B , researchers found that diterpene compounds displayed significant antiproliferative activity; among them DD1 showed outstanding inhibition ability capable to induce apoptosis effectively while suppressing organoid growth derived from prostate cancer patients. To further evaluate DD1’s therapeutic potential multiple levels pharmacodynamic validation were conducted revealing that not only does it inhibit conventional CRPC cell lines but also exhibits good antitumor activity against various clinically isolated resistant CRPC cells . Notably ,DD1 could significantly inhibit tumor growth without observable toxicity reactions providing solid groundwork for its development into an anti-CRPC drug .
Target Selection & Molecular Mechanism Study
To elucidate DD1’s mechanism action ,the research team employed Activity-Based Protein Profiling(ABPP) technology targeting selection process designing two biotin-labeled photoaffinity probes:DD1-Bio-PT1&DD1-Bio -PT2 respectively carrying diazabicyclo[3 .3 .0]octane &phenyl azide photolabels.Cellular assays confirmed these probes retained similar antiproliferative activities compared to parent compound . nThrough comprehensive target identification workflow involving cross-link reaction cellular lysis streptavidin bead enrichment trypsin digestion LC-MS/MS detection etc.,the research group ultimately identified nuclear transport protein importin -βl directly targeted by DDl.Follow-up competitive pull-down experiment CETSA surface plasmon resonance(SPR)and other techniques validated this discovery.Molecular docking residue mutation experiments further revealed that ddI primarily acts upon importin β-l protein c-terminal amino acid region550–876 where Gln560 Phe577 Leu580 serve critical binding sites.. n ### Role Mechanism Of Importin βl In Crpc nAnalysis through TCGA database immunohistochemistry experiments revealed significant high expression levels importinin-betal tissues correlated positively disease stages Gleason scores metastasis degrees indicating potentially crucial role played during progression crpc ..Gene knockout tests demonstrated downregulating KPNB gene encoding importinin-beta results inhibiting proliferation crpc while ddI no longer exhibited additional suppression post-knockout confirming direct involvement viaimportinin-beta pathway leading towards anticancer effect.Additional proteomics transcriptomics analyses suggestedddI inhibits function affecting several key drivers’ nuclear translocation processes thereby exerting antitumor actions... n ### Significance Future Prospects Of The Study...This study holds substantial scientific significance clinical value firstly clarifying importance regarding identifying novel targets likeimportinn beta-one overcoming current therapies resistances secondly validating active components within traditional medicines showcasing modernization efforts alongside establishing methodological frameworks applicable across diverse areas ensuring successful integration practices ...Future investigations may explore optimizing structures enhancing selectivity pharmacokinetic characteristics meanwhile delving deeper into understanding biological functionalities surrounding imports impacting overall outcomes developing more effective combination strategies thus presenting breakthrough candidates advancing modernized approaches supporting health initiatives globally!... n ### Challenges Opportunities Facing Traditional Medicine Modernization ...Identifying active component targets remains pivotal challenge faced throughout ongoing modernization endeavors amid complexities inherent multi-component interactions prevalent amongst herbal remedies...Emerging methodologies utilizing click chemistry-based profiling present revolutionary advancements aiding progress towards resolving aforementioned issues ....Our findings demonstrate comprehensive strategic framework encompassing steps ranging sourcing verifying efficacies identifying molecular interactions substantiating correlations leading finally elucidating downstream pathways promoting robust technological avenues paving way forward enhancing global acceptance integrating holistic paradigms improving human welfare...