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YPD-30, a prodrug of YPD-29B, is an oral small-molecule inhibitor targeting PD-L1 for the treatment of human cancer

Acta Pharmaceutica Sinica B 2022年第6期12卷 2845-2858页

作者： Fangfang Lai Ming Ji Lei Huang Yunchen Wang Nina Xue Tingting Du Kai Dong Xiaoqing Yao Jing Jin Zhiqiang Feng Xiaoguang Chen Department of Pharmacology State Key Laboratory of Bioactive Substances and Functions of Natural MedicinesInstitute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Department of Pharmacochemistry Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Tianjin Chase Sun Pharmaceutical Co. Ltd.Tianjin 300170China

PD-1 and PD-L1 antibodies have brought about extraordinary clinical benefits for cancer patients,and their indications are expanding ***,most PD-1/PD-L1 agents are administered intravenously,which may be uncomfortable for some cancer ***,we develop a novel oral-delivered small molecular,YPD-29B,which specifically targets human *** data suggested that YPD-29B could potently and selectively block the interaction between PD-L1 and PD-1,but did not inhibit any other immune ***,YPD-29B induced human PD-L1 dimerization and internalization,which subsequently activated T lymphocytes and therefore overcomes immunity tolerance in ***-29B was modified as the YPD-30 prodrug to improve *** humanized mice with human PD-1 xenografts of human PD-L1 knock-in mouse MC38 cancer cells,we demonstrated that YPD-30 exhibited significant antitumor activity and was well tolerated in *** together,our results indicate that YPD-30 serves as a promising therapeutic candidate for anti-human PD-L1 cancer immunotherapy.

关键词： PD-L1 Small molecular inhibitor Prodrug Immune checkpoints Cancer immunotherapy

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S1PR1 serves as a viable drug target against pulmonary fibrosis by increasing the integrity of the endothelial barrier of the lung

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Acta Pharmaceutica Sinica B 2023年第3期13卷 1110-1127页

作者： Mengyao Hao Rong Fu Jun Tai Zhenhuan Tian Xia Yuan Yang Chen Mingjin Wang Huimin Jiang Ming Ji Fangfang Lai Nina Xue Liping Bai Yizhun Zhu Xiaoxi Lv Xiaoguang Chen Jing Jin State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaChinese Academy of Medical SciencesPeking Union Medical CollegeBeijing 100050China Department of Otolaryngology Head and Neck SurgeryChildren's Hospital Capital Institute of PediatricsBeijing 100020China Department of Thoracic Surgery Peking Union Medical College HospitalPeking Union Medical CollegeDong Cheng DistrictBeijing 100730China State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191China Department of Pharmacology School of PharmaceuticalGuangzhou University of Chinese MedicineGuangzhou 510000China State Key Laboratory of Quality Research in Chinese Medicine Macao Institute for Applied Research in Medicine and HealthMacao University of Science and TechnologyTaipaMacao SAR 999078China

Idiopathic pulmonary fibrosis(IPF)is a progressive lung disease with unclear etiology and limited treatment *** median survival time for IPF patients is approximately 2–3 years and there is no effective intervention to treat IPF other than lung *** important components of lung tissue,endothelial cells(ECs)are associated with pulmonary ***,the role of endothelial dysfunction in pulmonary fibrosis(PF)is incompletely ***-1-phosphate receptor 1(S1PR1)is a G protein-coupled receptor highly expressed in lung *** expression is markedly reduced in patients with ***,we generated an endothelial-conditional S1pr1 knockout mouse model which exhibited inflammation and fibrosis with or without bleomycin(BLM)*** activation of S1PR1 with an S1PR1 agonist,IMMH002,exerted a potent therapeutic effect in mice with bleomycin-induced fibrosis by protecting the integrity of the endothelial *** results suggest that S1PR1 might be a promising drug target for IPF therapy.

关键词： Idiopathic pulmonary fibrosis Endothelial barrier Tight junction Sphingosine-1-phosphate receptor 1 Sphingosine-1-phosphate receptor 1 agonist FTY720 IMMH002 Protein stability

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Advances in development of antiviral strategies against respiratory syncytial virus

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Acta Pharmaceutica Sinica B 2025年第4期15卷 1752-1772页

作者： Yang, Ge Jiang, Guangyu Jiang, Jiandong Li, Yuhuan State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050 China CAMS Key Laboratory of Antiviral Drug Research Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050 China Beijing Key Laboratory of Antimicrobial Agents Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050 China NHC Key Laboratory of Biotechnology for Microbial Drugs Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050 China

Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in infants and young children, as well as an important cause of respiratory tract infections in immunocompromised patients and the elderly, which poses a significant economic and social burden worldwide. In recent years, substantial progress has been made in understanding the structure and function of RSV proteins and the interactions between RSV with host factors which is helpful to the discovery of new therapeutic targets and the development of novel interventions. Although two vaccines and two monoclonal antibodies for RSV prevention have been approved, the antiviral treatment remains an unmet clinical need. In this review, we summarize the structure, protein functional properties, and pathological mechanisms of RSV and the current status of RSV drug development. In addition, remaining challenges and innovative ideas for RSV prevention and treatment have also been highlighted. © 2025 The Authors

关键词： Antivirals Drug development Infection New strategies Respiratory syncytial virus (RSV) Therapeutic targets Viral entry Viral replication

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A fundamental study on the fluorescence-quenching effect of nitro groups in tetraphenylethene AIE dyes with electron-withdrawing groups

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Chinese Chemical Letters 2021年第6期32卷 1925-1928页

作者： Cheng-Xiao Zhao Tian Liu Manyi Xu Hao Lin Chong-Jing Zhang State Key Laboratory of Bioactive Substance and Functions of Natural Medicines and Beijing Key Laboratory of Active Substances Discovery and Drugability Evaluation Institute of Materia MedicaPeking Union Medical College and Chinese Academy of Medical SciencesBeijing 100050China School of Pharmaceutical Science Shanxi Medical UniversityTaiyuan 030001China

A nitro group is a common fluorescence quencher,but its quenching efficiency can be easily affected by the surrounding *** date,there has been no systematic study on the effects of electronwithdrawing groups on the quenching efficiency of nitro ***,by virtue of experimental validation and theoretical calculations,we found that strong electron-withdrawing groups,such as pyridinium and dicyanovinyl groups,are detrimental to the quenching effect of nitro *** the electron-withdrawing ability could restore the nitro group’s quenching effect.

关键词： Fluorescence Aggregation-induced emission Quenching effect Nitro group

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miR-486-3p Suppresses Osteosarcoma Proliferation and Migration by Targeting the SPRED1-MAPK/ERK Pathway

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Biochemical Genetics 2025年 1-17页

作者： Zhang, Yu Zhou, Yi Zhang, Sen Zhang, Xiaoying Li, Jiaxin Zhan, Xiao-Kai Department of Orthopaedics The First People’s Hospital of Chengdu Sichuan Province Chengdu China State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100050 China Department of Gastrointestinal Surgery Lishui Hospital Affiliated of Wenzhou Medical University & Lishui City People’s Hospital Zhejiang Province Lishui China Department of Hematology and Oncology Beijing Chao-Yang Hospital Capital Medical University Beijing 100020 China

Osteosarcoma (OS) is a common malignancy of the bone that originates from stromal cell lines. One of the key cellular pathways extensively studied in OS is the mitogen-activated protein kinase (MAPK) pathway, particularly ERK1/2, whose activation is closely associated with tumor growth and metastasis. MicroRNA (miRNA)-based detection and targeted therapies offer promising new strategies for the treatment of OS. In this study, we investigated the role of miR‑486‑3p in the regulation of the ERK1/2 pathway in OS. We examined the expression level of miR‑486‑3p in the GEO dataset (GSE65071) and clinical samples, and analyzed its regulation of the target gene SPRED1 in OS cells and tumor-bearing mice. Downregulation of miR‑486‑3p was confirmed in OS tissues, with its expression decreasing in line with the progression of clinical stages. Furthermore, the exogenous introduction of a miR-486-3p mimic attenuated the malignant behavior of OS cells, inhibiting their proliferation, migration, and invasion. Bioinformatic analysis revealed that miR‑486‑3p directly targets SPRED1 in OS, leading to alterations in epithelial-to-mesenchymal transition (EMT) markers, including E-cadherin, N-cadherin, and Vimentin. Functional loss- and gain-of-function experiments confirmed that miR‑486‑3p directly targets SPRED1 and inactivates the ERK1/2 pathway in both OS cells and tumor-bearing mice. This review demonstrates that downregulation of miR-486-3p leads to increased SPRED1 expression, which activates the ERK1/2 pathway in OS. Targeting miR-486-3p and SPRED1 could offer potential therapeutic benefits. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2025.

关键词： ERK1/2 MAPK MiR‑486‑3p Osteosarcoma SPRED1

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A novel PI3K inhibitor XH30 suppresses orthotopic glioblastoma and brain metastasis in mice models

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Acta Pharmaceutica Sinica B 2022年第2期12卷 774-786页

作者： Ming Ji Dongjie Wang Songwen Lin Chunyang Wang Ling Li Zhihui Zhang Jing Jin Deyu Wu Yi Dong Heng Xu Duo Lu Xiaoguang Chen State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

Glioblastoma is carcinogenesis of glial cells in central nervous system and has the highest incidence among primary brain *** metastasis,such as breast cancer and lung cancer,also leads to high *** available medicines are limited due to blood-brain *** activation of phosphatidylinositol 3-kinases(PI3 K)signaling pathway is prevalent in glioblastoma and metastatic ***,we characterized a 2-amino-4-methylquinazoline derivative XH30 as a potent PI3 K inhibitor with excellent anti-tumor activity against human ***30 significantly repressed the proliferation of various brain cancer cells and decreased the phosphorylation of key proteins of PI3 K signaling pathway,induced cell cycle arrest in G1 phase as ***,XH30 inhibited the migration of glioma cells and blocked the activation of PI3 K pathway by interleukin-17 A(IL-17 A),which increased the migration of U87 *** administration of XH30 significantly suppressed the tumor growth in both subcutaneous and orthotopic tumor ***30 also repressed tumor growth in brain metastasis models of lung ***,XH30 reduced IL-17 A and its receptor IL-17 RA in *** results indicate that XH30 might be a potential therapeutic drug candidate for glioblastoma migration and brain metastasis.

关键词： Glioblastoma Brain metastasis PI3K-mTOR-AKT signaling pathway PI3K inhibitor IL-17A

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Chemokine-like factor 1 (CKLF1) is expressed in myocardial ischemia injury in vivo and in vitro

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BIOCELL 2024年第6期48卷 981-990页

作者： JULING FENG HAODONG CHEN YANGBO LIU QIDI AI YANTAO YANG LEI ZHAO SHIFENG CHU NAIHONG CHEN School of Pharmacy Department of PharmacyHunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction PiecesHunan University of Chinese MedicineChangsha410208China Department of Pharmacology State Key Laboratory of Bioactive Substances and Functions of Natural MedicinesInstitute of Materia Medica&Neuroscience CenterChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100050China Department of Diagnostics Research Lab of Translational Medicine Hengyang Medical CollegeUniversity of South ChinaHengyang421001China Department of Gastrointestinal Surgery The First Affiliated HospitalHengyang Medical CollegeUniversity of South ChinaHengyang421001China

Introduction:Chemokine-like factor 1(CKLF1)is a chemokine that is overexpressed in several *** previousﬁndings revealed a signiﬁcant increase in CKLF1 expression in the ischemic brain,suggesting its potential as a therapeutic target for ischemic ***:In this study,we examined the expression dynamics of CKLF1 in both in vivo and in vitro models of ischemic cardiac *** infarction(MI)was induced in vivo by ligation of the left anterior descending artery(LAD)of the rat *** levels of CKLF1,Creatine Kinase MB Isoenzyme(CK-MB),and Lactate dehydrogenase(LDH)in the serum were detected using Enzyme-linked immunosorbent assay(ELISA).The expression of CKLF1 in the infarcted area was detected by immunohistochemistry,immunoﬂuorescence,quantitative PCR(qPCR),and Western blotting(WB).H9C2 and AC16 cardiomyocytes cultured in vitro were subjected to oxygen and glucose deprivation(OGD).LDH was used to detect cell damage,and CKLF1 expression was detected by qPCR and ***:CKLF1 mRNA and protein expression were signiﬁcantly increased in h9c2 cells at 1.5 h and in AC16 cells at 4 h after *** serum CK-MB in rats increased signiﬁcantly on theﬁrst day after infarction,while the LDH concentration increased signiﬁcantly on the third day after ***1 blood levels signiﬁcantly increased on theﬁrst day following MI in ***1 expression notably increased in the infarct area on days 1,3,and 7 *** MI tissue,CKLF1 colocalizes with cardiomyocytes,macrophages,and ***:CKLF1 was substantially expressed during myocardial ischemia injury both in vivo and in vitro and was colocalized with macrophages and neutrophils,indicating that CKLF1 is expected to be a biomarker and a drug target for the treatment of myocardial infarction.

关键词： Chemokine-like factor 1 Overexpression Myocardial infarction

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TIMP1 preserves the blood-brain barrier through interacting with CD63/integrin β1 complex and regulating downstream FAK/RhoA signaling

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Acta Pharmaceutica Sinica B 2020年第6期10卷 987-1003页

作者： Jingshu Tang Yuying Kang Longjian Huang Lei Wu Ying Peng State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China

Blood-brain barrier(BBB)breakdown and the associated microvascular hyperpermeability are hallmark features of several neurological disorders,including traumatic brain injury(TBI).However,there is no viable therapeutic strategy to rescue BBB *** inhibitor of metalloproteinase-1(TIMP1)has been considered to be beneficial for vascular integrity,but the molecular mechanisms underlying the functions of TIMP1 remain ***,we report that TIMP1 executes a protective role on neuroprotective function via ameliorating BBB disruption in mice with experimental *** human brain microvessel endothelial cells(HBMECs)exposed to hypoxia and inflammation injury,the recombinant TIMP1(rTIMP1)treatment maintained integrity of junctional proteins and trans-endothelial ***,TIMP1 interacts with CD63/integrinβ1 complex and activates downstream FAK signaling,leading to attenuation of RhoA activation and F-actin depolymerization for endothelial cells structure ***,these effects depend on CD63/integrinβ1 complex,instead of the MMP-inhibitory ***,our results identified a novel MMP-independent function of TIMP1 in regulating endothelial barrier *** interventions targeting TIMP1 and its downstream signaling may be beneficial to protect BBB function following brain injury and neurological disorders.

关键词： Tissue inhibitor of metalloproteinase-1 Blood-brain barrier Junctional proteins CD63 Integrinβ1

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Identifying genetic targets in clinical subtypes of Parkinson’s disease for optimizing pharmacological treatment strategies

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Signal Transduction and Targeted Therapy 2024年第12期9卷 5708-5719页

作者： Dewen Kong Cao Li LingYan Ma Lida Du Nan Jiang Xiaoyue Zhao Sen Zhang Zhigang Zhao Lianhua Fang Guanhua Du State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Beijing Key Laboratory of Drug Target Identification and Drug ScreeningInstitute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina Department of Pharmacy Beijing Tiantan HospitalCapital Medical UniversityBeijingChina Center for Movement Disorders Department of NeurologyBeijing Tiantan HospitalCapital Medical UniversityBeijingChina China National Clinical Research Center for Neurological Diseases BeijingChina Institute of Molecular Medicine&Innovative Pharmaceutics Qingdao UniversityQingdaoChina School of Pharmacy Henan UniversityKaifengChina Medical Science Research Center Peking Union Medical College HospitalChinese Academy of Medical Science and Peking Union Medical CollegeBeijingChina

The heterogeneity of Parkinson’s disease(PD)has been recognized in clinical,with patients categorized into distinct subsets based on motor phenotype,such as tremor-dominant PD(TD),postural instability and gait difficulty-dominant PD(PIGD)and mixed PD(Mix).Despite this categorization,the underlying mechanisms of this heterogeneity remain poorly understood,and there is no personalized effective treatment for each PD *** address this,a rat model for PD subtypes was established by unilateral stereotaxic injection of 6-OHDA,followed by cluster analysis of behavioral *** serum neurofilament light chain(NfL)and uric acid(UA)levels as well as alterations in brain autonomic activity in rats were consistent with clinical patients,and metabolomics results showed that more than 70%of the metabolites in the serum of different subtypes of PD rats and clinical patients appeared to be consistently *** transcriptomic analysis by RNA-seq has elucidated that the development of PD subtypes is associated with altered gene expression in neurotransmitter,neuronal damage in the central or peripheral nervous system,and lipid *** addition,based on the subtype-specific differentially expressed genes,25 potential drug candidates were ***,the Alox15 inhibitor baicalein showed a greater efficacy on Mix rats,highlighting the possibility of selecting targeted treatments for well-defined individuals.

关键词： clinical subtypes alterations

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New seco-dibenzocyclooctadiene lignans with nitric oxide production inhibitory activity from the roots of Kadsura longipedunculata

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Chinese Chemical Letters 2020年第2期31卷 423-426页

作者： Xinzhu Qi Jiabao Liu Jiabao Chen Qi Hou Shuai Li State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

Four new seco-dibenzocyclooctadiene lignans,kadlongilignans A-D(1-4),consisting of a rare 6,7-seco-(1),two 15,16-seco-(2 and 3) and a 9,10-seco-dibenzocyclooctadiene(4) lignans,were isolated from the roots of Kadsura *** structures were elucidated by spectroscopic analysis,including extensive NM R,MS and ECD(electronic circular dichroism) *** 3 and 4 exhibited potent inhibitory activities against NO(nitric oxide) production of LPS(lipopolysaccharide)-induced murine macrophages with the inhibition rates of 36.3% and 26.9%,respectively.

关键词： Kadsura longipedunculata Seco-dibenzocyclooctadiene lignans Kadlongilignans A-D Spectroscopic analysis NO production inhibition

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