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Opportunities and challenges of incretin-based hypoglycemic agents treating type 2 diabetes mellitus from the perspective of physiological disposition

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药学学报:英文版 2023年第6期13卷 2383-2402页

作者： Yaochen Xie Qian Zhou Qiaojun He Xiaoyi Wang Jincheng Wang Center for Drug Safety Evaluation and Research Zhejiang Province Key Laboratory of Anti-Cancer Drug ResearchCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310007China Department of Pharmacy Hangzhou Medical CollegeHangzhou 310053China Department of Nephrology the First Affiliated Hospital of Huzhou Teachers Collegethe First People's Hospital of HuzhouHangzhou 313000China

The treatment of patients with diabetes mellitus, which is characterized by defective insulin secretion and/or the inability of tissues to respond to insulin, has been studied for decades. Many studies have focused on the use of incretin-based hypoglycemic agents in treating type 2 diabetes mellitus(T2DM). These drugs are classified as GLP-1 receptor agonists, which mimic the function of GLP-1,and DPP-4 inhibitors, which avoid GLP-1 degradation. Many incretin-based hypoglycemic agents have been approved and are widely used, and their physiological disposition and structural characteristics are crucial in the discovery of more effective drugs and provide guidance for clinical treatment of T2DM.here, we summarize the functional mechanisms and other information of the drugs that are currently approved or under research for T2DM treatment. In addition, their physiological disposition, including metabolism, excretion, and potential drug drug interactions, is thoroughly reviewed. We also discuss similarities and differences in metabolism and excretion between GLP-1 receptor agonists and DPP-4 inhibitors. This review may facilitate clinical decision making based on patients' physical conditions and the avoidance of drug drug interactions. Moreover, the identification and development of novel drugs with appropriate physiological dispositions might be inspired.

关键词： T2DM Incretins-based hypoglycemic agents GLP-1 receptor agonists DPP-4 inhibitors Physiological disposition Metabolism Excretion Drug drug interactions

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Deubiquitination complex platform:A plausible mechanism for regulating the substrate specificity of deubiquitinating enzymes

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药学学报:英文版 2023年第7期13卷 2955-2962页

作者： Yi-Zheng Fang Li Jiang Qiaojun He Ji Cao Bo Yang Institute of Pharmacology and Toxicology Zhejiang Province Key Laboratory of Anti-Cancer Drug ResearchCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China The Innovation Institute for Artificial Intelligence in Medicine Zhejiang UniversityHangzhou 310018China Cancer Center of Zhejiang University Hangzhou 310058China Center for Drug Safety Evaluation and Research of Zhejiang University Hangzhou 310058China

Deubiquitinating enzymes(DUBs) or deubiquitinases facilitate the escape of multiple proteins from ubiquitin-proteasome degradation and are critical for regulating protein expression levels in vivo.Therefore,dissecting the underlying mechanism of DUB recognition is needed to advance the development of drugs related to DUB signaling pathways.To data,extensive studies on the ubiquitin chain specificity of DUBs have been reported,but substrate protein recognition is still not clearly understood.As a breakthrough,the scaffolding role may be significant to substrate protein selectivity.From this perspective,we systematically characterized the scaffolding proteins and complexes contributing to DUB substrate selectivity.Furthermore,we proposed a deubiquitination complex platform(DCP) as a potentially generic mechanism for DUB substrate recognition based on known examples,which might fill the gaps in the understanding of DUB substrate specificity.

关键词： Deubiquitinating enzyme(DUB) Deubiquitination Substrate specificity Complex Scaffold Protein partner

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Targeting PI3K/AKT signaling for treatment of idiopathic pulmonary fibrosis

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Acta Pharmaceutica Sinica B 2022年第1期12卷 18-32页

作者： Jincheng Wang Kaili Hu Xuanyan Cai Bo Yang Qiaojun He Jiajia Wang Qinjie Weng Center for Drug Safety Evaluation and Research College of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058 Hangzhou Institute of Innovative Medicine College of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058

Idiopathic pulmonary fibrosis(IPF) is a chronic progressive fibrotic interstitial pneumonia with unknown causes. The incidence rate increases year by year and the prognosis is poor without cure.Recently, phosphatidylinositol 3-kinase(PI3 K)/protein kinase B(PKB/AKT) signaling pathway can be considered as a master regulator for IPF. The contribution of the PI3 K/AKT in fibrotic processes is increasingly prominent, with PI3 K/AKT inhibitors currently under clinical evaluation in IPF. Therefore,PI3 K/AKT represents a critical signaling node during fibrogenesis with potential implications for the development of novel anti-fibrotic strategies. This review epitomizes the progress that is being made in understanding the complex interpretation of the cause of IPF, and demonstrates that PI3 K/AKT can directly participate to the greatest extent in the formation of IPF or cooperate with other pathways to promote the development of fibrosis. We further summarize promising PI3 K/AKT inhibitors with IPF treatment benefits, including inhibitors in clinical trials and pre-clinical studies and natural products, and discuss how these inhibitors mitigate fibrotic progression to explore possible potential agents, which will help to develop effective treatment strategies for IPF in the near future.

关键词： Idiopathic pulmonary fibrosis PI3K/AKT signaling Pathogenesis Coagulation cascade Immune activation Fibroblast accumulation Therapeutic target Drug therapy

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Macrophage senescence in health and diseases

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1508-1524页

作者： Longling Wang Wenxiang Hong Hong Zhu Qiaojun He Bo Yang Jiajia Wang Qinjie Weng Center for Drug Safety Evaluation and Research Zhejiang Province Key Laboratory of Anti-Cancer Drug ResearchCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China Nanhu Brain-Computer Interface Institute Hangzhou 311100China Taizhou Institute of Zhejiang University Taizhou 318000China The Second Affiliated Hospital Zhejiang University School of MedicineHangzhou 310009China

Macrophage senescence,manifested by the special form of durable cell cycle arrest and chronic low-grade inflammation like senescence-associated secretory phenotype,has long been consid-ered harmful.Persistent senescence of macrophages may lead to maladaptation,immune dysfunction,and finally the development of age-related diseases,infections,autoimmune diseases,and malignancies.However,it is a ubiquitous,multi-factorial,and dynamic complex phenomenon that also plays roles in remodeled processes,including wound repair and embryogenesis.In this review,we summarize some general molecular changes and several specific biomarkers during macrophage senescence,which may bring new sight to recognize senescent macrophages in different conditions.Also,we take an in-depth look at the functional changes in senescent macrophages,including metabolism,autophagy,polarization,phagocytosis,antigen presentation,and infiltration or recruitment.Furthermore,some degenerations and diseases associated with senescent macrophages as well as the mechanisms or relevant genetic regulations of senescent macrophages are integrated,not only emphasizing the possibility of regulating macrophage senescence to benefit age-associated diseases but also has an implication on the finding of potential tar-gets ordrugs clinically.

关键词： Macrophages Senescence Molecular changes Functional alterations Aging tissues Age-associated diseases Drug treatment Genetic regulation

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The regulatory and modulatory roles of TRP family channels in malignant tumors and relevant therapeutic strategies

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1761-1780页

作者： Tiecheng Zhong Wenxin Zhang Hongjie Guo Xiaohui Pan Xi Chen Qiaojun He Bo Yang Ling Ding Zhejiang Province Key Laboratory of Anti-Cancer Drug Research Institute of Pharmacology and ToxicologyCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China

Transient receptor potential(TRP)channels are one primary type of calcium(Ca^(2+))permeable channels,and those relevant transmembrane and intracellular TRP channels were previously thought to be mainly associated with the regulation of cardiovascular and neuronal systems.Nowadays,however,accumulating evidence shows that those TRP channels are also responsible for tumorigenesis and progression,inducing tumor invasion and metastasis.However,the overall underlying mechanisms and possible signaling transduction pathways that TRP channels in malignant tumors might still remain elusive.Therefore,in this review,we focus on the linkage between TRP channels and the significant characteristics of tumors such as multi-drug resistance(MDR),metastasis,apoptosis,proliferation,immune surveillance evasion,and the alterations of relevant tumor micro-environment.Moreover,we also have discussed the expression of relevant TRP channels in various forms of cancer and the relevant inhibitors’efficacy.The chemo-sensitivity of the anti-cancer drugs of various acting mechanisms and the potential clinical applications are also presented.Furthermore,it would be enlightening to provide possible novel therapeutic approaches to counteract malignant tumors regarding the intervention of calcium channels of this type.

关键词： TRP channels Cancer progression Tumor microenvironment Tumor-associated immunocytes Intracellular mechanism Programmed cancer cell death Targeted tumor therapy

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The impact of lipids on the cancer—immunity cycle and strategies for modulating lipid metabolism to improve cancer immunotherapy

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Acta Pharmaceutica Sinica B 2023年第4期13卷 1488-1497页

作者： Mingming Zheng Wenxin Zhang Xi Chen Hongjie Guo Honghai Wu Yanjun Xu Qiaojun He Ling Ding Bo Yang Zhejiang Province Key Laboratory of Anti-Cancer Drug Research Institute of Pharmacology and ToxicologyCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China Department of Medical Thoracic Oncology the Cancer Hospital of University of Chinese Academy of Sciences(Zhejiang Cancer Hospital)Chinese Academy of SciencesHangzhou 310022China The Innovation Institute for Artificial Intelligence in Medicine Zhejiang UniversityHangzhou 310018China Cancer Center of Zhejiang University Hangzhou 310058China

Lipids have been found to modulate tumor biology,including proliferation,survival,and metastasis.With the new understanding of tumor immune escape that has developed in recent years,the influence of lipids on the cancer—immunity cycle has also been gradually discovered.First,regarding antigen presentation,cholesterol prevents tumor antigens from being identified by antigen presenting cells.Fatty acids reduce the expression of major histocompatibility complex class I and costimulatory factors in dendritic cells,impairing antigen presentation to T cells.Prostaglandin E2(PGE2)reduce the accumulation of tumor-infiltrating dendritic cells.Regarding T-cell priming and activation,cholesterol destroys the structure of the T-cell receptor and reduces immunodetection.In contrast,cholesterol also promotes T-cell receptor clustering and relative signal transduction.PGE2 represses T-cell proliferation.Finally,regarding T-cell killing of cancer cells,PGE2 and cholesterol weaken granule-dependent cytotoxicity.Moreover,fatty acids,cholesterol,and PGE2 can improve the activity of immunosuppressive cells,increase the expression of immune checkpoints and promote the secretion of immunosuppressive cytokines.Given the regulatory role of lipids in the cancer—immunity cycle,drugs that modulate fatty acids,cholesterol and PGE2 have been envisioned as effective way in restoring antitumor immunity and synergizing with immunotherapy.These strategies have been studied in both preclinical and clinical studies.

关键词： Lipids Fatty acids Cholesterol Prostaglandin E2 Tumor immune escape Cancer—immunity cycle Immunotherapy Combination therapy

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Phosphorylation regulates cullin-based ubiquitination in tumorigenesis

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Acta Pharmaceutica Sinica B 2021年第2期11卷 309-321页

作者： Yifan Chen Xuejing Shao Ji Cao Hong Zhu Bo Yang Qiaojun He Meidan Ying Zhejiang Province Key Laboratory of Anti-Cancer Drug Research College of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China

Cullin-RING ligases(CRLs)recognize and interact with substrates for ubiquitination and degradation,and can be targeted for disease treatment when the abnormal expression of substrates involves pathologic processes.Phosphorylation,either of substrates or receptors of CRLs,can alter their interaction.Phosphorylation-dependent ubiquitination and proteasome degradation influence various cellular processes and can contribute to the occurrence of various diseases,most often tumorigenesis.These processes have the potential to be used for tumor intervention through the regulation of the activities of related kinases,along with the regulation of the stability of specific oncoproteins and tumor suppressors.This review describes the mechanisms and biological functions of crosstalk between phosphorylation and ubiquitination,and most importantly its influence on tumorigenesis,to provide new directions and strategies for tumor therapy.

关键词： Phosphorylation Cullin-RING ligases Ubiquitination Tumorigenesis Targeted therapy Degradation Crosstalk Kinases

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Yes-associated protein(YAP)and transcriptional coactivator with a PDZ-binding motif(TAZ):a nexus between hypoxia and cancer

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Acta Pharmaceutica Sinica B 2020年第6期10卷 947-960页

作者： Chenxi Zhao Chenming Zeng Song Ye Xiaoyang Dai Qiaojun He Bo Yang Hong Zhu Zhejiang Province Key Laboratory of Anti-Cancer Drug Research College of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China Department of hepatobiliary and Pancreatic Surgery the Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou 310009China Center for Drug Safety Evaluation and Research of Zhejiang University Hangzhou 310058China

Hypoxia is a common feature of solid tumors.As transcription factors,hypoxia-inducible factors(HIFs)are the master regulators of the hypoxic microenvironment;their target genes function in tumorigenesis and tumor development.Intriguingly,both yes-associated protein(YAP)and its paralog transcriptional coactivator with a PDZ-binding motif(TAZ)play fundamental roles in the malignant progression of hypoxic tumors.As downstream effectors of the mammalian Hippo pathway,YAP and/or TAZ(YAP/TAZ)are phosphorylated and sequestered in the cytoplasm by the large tumor suppressor kinase 1/2(LATS1/2)-MOB kinase activator 1(MOB 1)complex,which restricts the transcriptional activity of YAP/TAZ.However,dephosphorylated YAP/TAZ have the ability to translocate to the nucleus where they induce transcription of target genes,most of which are closely related to cancer.herein we review the tumor-related signaling crosstalk between YAP/TAZ and hypoxia,describe current agents and therapeutic strategies targeting the hypoxia-YAP/TAZ axis,and highlight questions that might have a potential impact in the future.

关键词： YAP TAZ HIFs Hypoxia Solid tumor

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Cyclin-dependent kinases-based synthetic lethality: Evidence, concept, and strategy

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Acta Pharmaceutica Sinica B 2021年第9期11卷 2738-2748页

作者： Kailin Li Jieqiong You Qian Wu Wen Meng Qiaojun He Bo Yang Chengliang Zhu Ji Cao College of Pharmaceutical Sciences Zhejiang UniversityHangzhou 310058China Innovation Institute for Artificial Intelligence in Medicine Zhejiang UniversityHangzhou 310058China Affiliated Hangzhou First People’s Hospital Zhejiang University School of MedicineHangzhou 310058China Cancer Center of Zhejiang University Hangzhou 310058China

Synthetic lethality is a proven effective antitumor strategy that has attracted great attention.Large-scale screening has revealed many synthetic lethal genetic phenotypes,and relevant smallmolecule drugs have also been implemented in clinical practice.Increasing evidence suggests that CDKs,constituting a kinase family predominantly involved in cell cycle control,are synthetic lethal factors when combined with certain oncogenes,such as MFC,TP53,and RAS,which facilitate numerous antitumor treatment options based on CDK-related synthetic lethality.In this review,we focus on the synthetic lethal phenotype and mechanism related to CDKs and summarize the preclinical and clinical discoveries of CDK inhibitors to explore the prospect of CDK inhibitors as antitumor compounds for strategic synthesis lethality in the future.

关键词： Synthetic lethality Cyclin-dependent kinase Antitumor therapy Oncogenes MYC P53 RAS PARP

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Epigenetic strategies synergize with PD-L1/PD-1 targeted cancer immunotherapies to enhance antitumor responses

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Acta Pharmaceutica Sinica B 2020年第5期10卷 723-733页

作者： Xi Chen Xiaohui Pan Wenxin Zhang Hongjie Guo Shuyuan Cheng Qiaojun He Bo Yang Ling Ding Zhejiang Province Key Laboratory of Anti-Cancer Drug Research Institute of Pharmacology and ToxicologyCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China

Immunotherapy strategies targeting the programmed cell death ligand 1(PD-L1)/programmed cell death 1(PD-1)pathway in clinical treatments have achieved remarkable success in treating multiple types of cancer.However,owing to the heterogeneity of tumors and individual immune systems,PD-L1/PD-1 blockade still shows slow response rates in controlling malignancies in many patients.Accumulating evidence has shown that an effective response to anti-PD-Ll/anti-PD-1 therapy requires establishing an integrated immune cycle.Damage in any step of the immune cycle is one of the most important causes of immunotherapy failure.Impairments in the immune cycle can be restored by epigenetic modification,including reprogramming the environment of tumor-associated immunity,eliciting an immune response by increasing the presentation of tumor antigens,and by regulating T cell trafficking and reactivation.Thus,a rational combination of PD-L1/PD-1 blockade and epigenetic agents may offer great potential to retrain the immune system and to improve clinical outcomes of checkpoint blockade therapy.

关键词： Epigenetic regulation Immune cycle PD-L1PD-1 blockade Cancer Immunotherapy

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