Journal of Chinese Pharmaceutical Sciences

Cutting-Edge FAK-targeting PROTACs: design, synthesis, and biological evaluation

Ruifeng Wang, Xin Zhao, Hongbao Hou, Ke Chen, Shuihua Liu, Ruyue Ren, Yunfeng Liu, Yi Zhang

2024, 33(9): 767-782. DOI: 10.5246/jcps.2024.09.057

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Focal adhesion kinase (FAK) is an intracellular tyrosine kinase that plays a critical role in the occurrence, development, and metastasis of cancer through both its kinase-dependent catalytic functions and kinase-independent scaffolding functions. Current kinase inhibitors target only its catalytic activity, leaving the scaffolding functions unaffected. However, proteolysis targeting chimeras (PROTACs) offers a promising approach by degrading the entire FAK protein, thereby inhibiting both functions simultaneously. In this study, we designed and synthesized novel PROTAC degraders, utilizing a defactinib derivative (compound 12) as the FAK ligand and a lenalidomide analog as the E3 ligase ligand. The structures of these compounds were confirmed through ¹H NMR, ¹³C NMR, and high-resolution mass spectrometry (HRMS). Among the synthesized compounds, the optimized compound 16b exhibited potent degradation activity against FAK protein in A549 cells, with a DC₅₀ of 6.16 ± 1.13 nM, significantly inhibiting the proliferation and colony formation of these cells. Compared to defactinib, 16b showed enhanced inhibition of A549 cell migration and invasion. Furthermore, our research demonstrated that the rapid and effective FAK degradation induced by 16b was mediated by a CRBN-dependent proteasome mechanism.

Wuling powder alleviates depressive-like behavior by attenuating endoplasmic reticulum stress in the mouse hippocampus

Lu Feng, Wei Huang, Ji Zheng, Dongmei Li, Mingyang Wang, Junya Liu, Shujie Fan, Chao Ji, Nan Yang, Yanyong Liu

2024, 33(9): 783-794. DOI: 10.5246/jcps.2024.09.058

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The response to endoplasmic reticulum (ER) stress has been noted in both human depression cases and depression models in rodents. Wuling powder, derived from the mycelium of the esteemed fungus Xylaria Nigripes (Kl.) Sacc, has demonstrated efficacy in alleviating depressive symptoms. The purpose of this research was to explore the antidepressant properties of Wuling powder and its basic molecular effects, particularly regarding alterations in ER stress. A model of social defeat stress was created by introducing a mouse to the cage of an unfamiliar, hostile mouse for intervals of 5–10 min daily over a span of 10 d. Subsequently, the mice received oral doses of Wuling powder for 2 weeks. The social approach-avoidance assay was employed to evaluate signs of depression-like behaviors. Moreover, protein and gene expressions linked to ER stress triggered by social defeat were analyzed through Western blotting analysis and quantitative real-time PCR. The behavioral tests indicated that Wuling powder ameliorated behaviors associated with depression due to social defeat stress. Treatment with Wuling powder markedly reduced the increased levels of the 78-kDa glucose-regulated protein and protein disulfide isomerase caused by social defeat stress. It also diminished the expression of inositol-requiring enzyme 1α (IRE1α) and spliced X box-binding protein-1 (sXBP1) at the protein and mRNA levels. Furthermore, Wuling treatment notably decreased the levels of phosphorylated eukaryotic initiation factor 2 alpha kinase (P-eIF2α), activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), simultaneously enhancing the ratio of B-cell lymphoma 2 (Bcl-2) to Bcl-2-associated X protein (Bax). These results suggested that Wuling powder could alleviate ER stress and inhibit cell apoptosis in the hippocampus by inhibiting protein translation and synthesis, thereby attenuating depressive-like behavior.

Developmental endothelial locus-1 enhances ER calmodulin expression, mitigates ER stress, suppresses inflammation, and attenuates neuronal apoptosis

Hao Wang, Kangxue Chen, Yuyan Zhang, Kuijun Jiang, Zhonglei Sun

2024, 33(9): 795-804. DOI: 10.5246/jcps.2024.09.059

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This study aimed to investigate the impact of developmental endothelial locus-1 (Del-1) on sarcoplasmic reticulum Ca²⁺ ATPase 2 (SERCA2) and its potential effects on spinal cord injury (SCI). A total of 48 mice were randomly assigned to the sham group, SCI group, and SCI + CE group. Each group was further divided into two subgroups. The Del treatment subgroup received tail-vein injections of Del-1 (1 μg/d) for a consecutive week, while the other group was injected with an equivalent volume of normal saline. After 1 week of experimentation, the mice were euthanized, and the spinal cord was extracted for further analysis. Initially, the impact of Del-1 on SERCA2 in the spinal cord was assessed using western blotting analysis. Subsequently, the effects of Del-1 on stress, inflammation, and apoptosis in the endoplasmic reticulum (ER) of SCI mice were analyzed through Western blotting analysis and fluorescent TUNEL. Finally, the study utilized Western blotting analysis and fluorescent TUNEL analysis to examine the consequences of Del-1 blocking SERCA2 on ER stress, inflammation, and apoptosis in mice. The results revealed that Del-1 treatment significantly increased the expression of SERCA2 in the spinal cord (P < 0.01) and mitigated SCI-induced ER stress, inflammation, and neuronal apoptosis (P < 0.01). Blocking SERCA2 expression in the spinal cord of SCI mice promoted ER stress, inflammatory response, and neuronal cell apoptosis (P < 0.01). However, Del-1 treatment did not alleviate the effects of blocking SERCA2 on ER stress, inflammatory response, and neuronal cell apoptosis (P > 0.05). In conclusion, this study proposed that Del-1 could reduce ER stress, inflammatory response, and nerve cell apoptosis in spinal cord injury by enhancing the expression of SERCA2.

Deciphering the mechanism of Liu Wei Di Huang Wan in treating premature ovarian failure: a comprehensive exploration through network pharmacology and molecular docking analysis

Ping Shang, Lin Liu, Yi Fang

2024, 33(9): 805-818. DOI: 10.5246/jcps.2024.09.060

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Premature ovarian failure (POF) is a prevalent gynecological disorder with significant implications for the physical and mental well-being of affected individuals. Liu Wei Di Huang Wan (LWDHW), a Chinese herbal compound, has demonstrated efficacy in alleviating the effects of POF. However, the underlying mechanism of action of LWDHW remains unclear. This study aimed to elucidate the potential molecular mechanism of LWDHW in treating POF using network pharmacology and molecular docking techniques. The active ingredients of LWDHW were initially screened through the TCMSP platform. At the same time, the relevant target genes associated with POF were identified using databases such as Disgenet, TTD, Drugbank, GeneCards, OMIM, and PharmGKB. Data analysis was conducted using the R language, Cytoscape, and STRING to construct and analyze the traditional Chinese medicine (TCM) regulatory network and protein-protein interaction (PPI) network maps. Subsequently, GO and KEGG enrichment analyses were performed using the R language. Finally, molecular docking was carried out between the protein receptors of the core genes and the corresponding small-molecule ligands. The study revealed 49 components and 189 predicted targets (after de-duplication) of LWDHW, along with 4524 targets (after de-duplication) associated with POF. Through comparative analysis, 163 potential genes were identified as common targets of LWDHW and POF, participating in biological processes such as response to chemical substances, molecular function regulation, and signaling receptor binding. Key biological pathways implicated included the MAPK signaling pathway, IL-17 signaling pathway, and HIF-1 signaling pathway, among others. Molecular docking results demonstrated a robust binding ability between the core genes of LWDHW and their corresponding ingredients. In conclusion, this comprehensive analysis provided insights into the potential molecular mechanisms of LWDHW in treating POF. The identified common targets and associated pathways contributed to our understanding of how LWDHW exerted its therapeutic effects, paving the way for further research and clinical applications. It is worth noting that future studies with experimental validation and clinical trials are essential to confirm these findings and establish the safety and efficacy of LWDHW in the treatment of POF.

Integrated approach of network pharmacology and chemometrics for quality control of Chinese patent medicine: A case study on Huo-Luo-San

Meiling Zhu, Jirong Zhang, Qiurong Zhang, Yu Lin, Xiaoyan Li, Wen Xu, Wei Xu

2024, 33(9): 819-836. DOI: 10.5246/jcps.2024.09.061

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Traditional Chinese medicine (TCM) has garnered significant global interest owing to its multi-component and multi-target theoretical framework and extensive therapeutic efficacy. However, the identification of quality markers (Q-markers) remains a formidable challenge in TCM. Hence, this study aimed to integrate network pharmacology and chemometrics to identify Q-markers in Chinese patent medicine, with a focus on Huo-Luo-San (HLS) as a case study. HLS, a widely used powdered Chinese patent medicine in China, comprises a complex formula of 10 herbs, initially formulated during the Qing dynasty for treating fractures. Initially, 13 components, chlorogenic acid, typhaneoside, isorhamnetin-3-O-neohesperidoside, cynaroside, notoginsenoside R₁, ginsenoside Rg₁, baicalin, berberine hydrochloride, ginsenoside Rb₁, dehydrocostus lactone, dioscin, imperatorin, and costunolide, were selected as phytochemical markers for each herb based on the Chinese Pharmacopoeia (2020 version), forming the “Herbs-Compounds-targets” network of HLS using network pharmacology. Subsequently, employing network pharmacology, the 13 HLS components were quantified using UPLC-QqQ-MS. Chromatographic conditions were optimized on a Waters Cortecs C₁₈ column (2.1 mm × 100 mm, 1.6 μm) with a gradient elution comprising 0.1% formic acid in water and acetonitrile. Analyte detection was performed in the multiple-reaction monitoring mode, and the method underwent validation for linearity, detection limit, precision, repeatability, stability, and accuracy. The validated method was then utilized to analyze the 13 components in 15 batches of HLS samples. Chemometric techniques, including hierarchical cluster analysis, principal component analysis, orthogonal partial least squares projection discriminant analysis, and box map analyses, were subsequently employed to identify the Q-markers. Ultimately, six components, baicalin, notoginsenoside R₁, berberine hydrochloride, dioscin, imperatorin, and chlorogenic acid, were selected as Q-markers for HLS. The integration of network pharmacology with chemometrics represented a novel approach for selecting Q-markers in Chinese patent medicine.

Quantification of eight components in Paeonia lactiflora and Glycyrrhiza decoction using UHPLC-MS/MS

Hao Jiang, Yushu Guo, Chao Shi

2024, 33(9): 837-845. DOI: 10.5246/jcps.2024.09.062

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This study aimed to utilize ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) to analyze and quantify eight therapeutic components in Paeonia lactiflora and Glycyrrhiza decoction. The goal was to establish an accurate, efficient, and applicable method for determining the composition of this formula, providing a reference for its clinical application. Methanol was employed to extract the therapeutic components from Paeonia lactiflora and Glycyrrhiza decoction, forming the test sample solution. UHPLC-MS/MS technology was applied to separate and analyze the test samples. The results indicated that upon analysis, the eight reference standards exhibited excellent linear relationships, and the test samples remained stable within 24 h. The content of paeoniflorin, paeonolide, glycyrrhizic acid A, quercetin, chebulic acid, liquiritin, naringenin, and glycyrrhetic acid was determined to be 3.530 ± 0.124, 0.139 ± 0.006, 0.245 ± 0.008, 0.779 ± 0.026, 0.433 ± 0.021, 0.388 ± 0.018, 0.617 ± 0.013, and 0.081 ± 0.005 mg/mL, respectively. This study established that UHPLC-MS/MS analysis demonstrated high efficiency and broad applicability, reflecting the chemical composition characteristics of Paeonia lactiflora and Glycyrrhiza decoction. This research provided a quantitative analysis method for the eight therapeutic components in Paeonia lactiflora and Glycyrrhiza decoction, applicable to its clinical use and quality control.

Clinical efficacy of Salvia miltiorrhiza in pathological scar treatment: A systematic review and meta-analysis

Zhihong Song, Jinji Yang, Hongzhuang Zhang, Wenxia Fan, Anqi Zhu, Shaojie Li, Hao Fu

2024, 33(9): 846-856. DOI: 10.5246/jcps.2024.09.063

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To systematically assess the clinical efficacy of Salvia miltiorrhiza (SM) in treating pathological scars and provide a reference basis for scar pharmacotherapy, we conducted a comprehensive literature search in both English and Chinese databases from database inception to December 2022. Key search terms included Salvia miltiorhiza, cryptotanshinone, tanshinone IIA, sodium-tanshinol, compound Salvia miltiorrhiza dripping pills, cicatrix, cicatrices, and scar. The inclusion criteria encompassed all clinical randomized controlled studies on the treatment of pathological scars with SM, without regard to blinding or allocation concealment, as well as irrespective of patient nationality, race, or age. Data from the selected literature were subjected to analysis using RevMan 5.4 software, employing the standard mean difference or weighted mean difference for numerical variables and odds ratios (ORs) for dichotomous variables. Statistical significance was set at P < 0.05. Six eligible studies involving a total of 778 patients met the inclusion criteria. The analysis revealed a significant therapeutic efficacy with an OR of 3.83 (95% CI: 2.65–5.54), indicating a substantially higher therapeutic efficacy rate in SM group compared to the control group. Furthermore, the total effective rate of treatment exhibited an OR of 6.94 (95% CI: 2.53–19.06), signifying a significantly superior treatment outcome in SM group. Regarding scar scores, no significant improvement was observed in SM group compared to the control group after 3 months of treatment (mean difference [MD] = –0.96, 95% CI: –2.29–0.36). However, after 6 months of treatment, the scar score demonstrated a noteworthy improvement in SM group (MD = –1.37, 95% CI: –2.44 to –0.30) compared to the control group. In summary, this study affirmed that SM treatment markedly enhanced the therapeutic efficacy and overall treatment efficiency for clinical scar patients, underscoring its positive clinical therapeutic impact on scar patients.

The research teams of Prof. Tao Liu, Prof. Qian Peng and Prof. Xiaoding Lou have made important progress in the field of biological orthogonal reactions

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center

2024, 33(9): 857-859.

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The research teams of Prof. Tao Liu, Prof. Qian Peng and Prof. Xiaoding Lou have made important progress in the field of biological orthogonal reactions.

The research teams of Prof. Liqin Zhang, Prof. Zhenjun Yang, Prof. Zhiqi Zhang, and Prof. Ying Guo developed functional aptamers screening of nucleic acid and drug development platform

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center

2024, 33(9): 860-863.

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The research teams of Prof. Liqin Zhang, Prof. Zhenjun Yang, Prof. Zhiqi Zhang, and Prof. Ying Guo developed functional aptamers screening of nucleic acid and drug development platform.

The research team of Prof. Lei Miao developed Fibrosis Overexpression and Retention (FORT) strategy for the treatment of metabolic liver disease

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center

2024, 33(9): 864-870.

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The research team of Prof. Lei Miao developed Fibrosis Overexpression and Retention (FORT) strategy for the treatment of metabolic liver disease.

The research teams of Prof. Yimin Cui and Prof. Qian Xiang have made new progress on CDK4/6 inhibitors

Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center

2024, 33(9): 871-872.

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The research teams of Prof. Yimin Cui and Prof. Qian Xiang have made new progress on CDK4/6 inhibitors.

The research team of Prof. Yiguang Wang developed a new strategy to regulate the core components of nanoparticles to enhance tumor imaging

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center

2024, 33(9): 873-874.

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The research team of Prof. Yiguang Wang developed a new strategy to regulate the core components of nanoparticles to enhance tumor imaging.

Prof. Xinjing Tang and Dr. Qian Wang developed a miRNA-based PROTACs strategy to target the degradation of Lin28 protein for the combined breast cancer therapy

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center

2024, 33(9): 875-876.

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Prof. Xinjing Tang and Dr. Qian Wang developed a miRNA-based PROTACs strategy to target the degradation of Lin28 protein for the combined breast cancer therapy.

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