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Tyrosine phosphatase SHP2 inhibitors in tumor-targeted therapies

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Acta Pharmaceutica Sinica B 2021年第1期11卷 13-29页

作者： Zhendong Song Meijing Wang Yang Ge Xue-Ping Chen Ziyang Xu Yang Sun Xiao-Feng Xiong Guangdong key laboratory of Chiral Molecule and Drug Discovery School of Pharmaceutical SciencesSun Yatsen UniversityGuangzhou 510006China state key laboratory of pharmaceutical biotechnology Department of Biotechnology and Pharmaceutical SciencesSchool of Life SciencesNanjing UniversityNanjing 210023China

Src homology containing protein tyrosine phosphatase 2(SHP2)represents a noteworthy target for various diseases,serving as a well-known oncogenic phosphatase in cancers.As a result of the low cell permeability and poor bioavailability,the traditional inhibitors targeting the protein tyrosine phosphate catalytic sites are generally suffered from unsatisfactory applied efficacy.Recently,a particularly large number of allosteric inhibitors with striking inhibitory potency on SHP2 have been identified.In particular,few clinical trials conducted have made significant progress on solid tumors by using SHP2 allosteric inhibitors.This review summarizes the development and structureeactivity relationship studies of the small-molecule SHP2 inhibitors for tumor therapies,with the purpose of assisting the future development of SHP2 inhibitors with improved selectivity,higher oral bioavailability and better physicochemical properties.

关键词： SHP2 Phosphatase Selectivity Allosteric inhibitor Tumor therapy

Study on the secondary metabolites of grasshopper-derived fungi Arthrinium sp.NF2410

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Chinese Journal of Natural Medicines 2020年第12期18卷 957-960页

作者： LI Wei WEI Jing CHEN Dao-Ying WANG Mei-Jing SUN Yang JIAO Fang-Wen JIAO Rui-Hua TAN Ren-Xiang GE Hui-Ming state key laboratory of pharmaceutical biotechnology Institute of Functional BiomoleculesSchool of Life SciencesNanjing UniversityNanjing 210023China state key laboratory of pharmaceutical biotechnology Department of Biotechnology and Pharmaceutical SciencesSchool of Life ScienceNanjing UniversityNanjing 210023China state key laboratory Cultivation Base for TCM Quality and Efficacy Nanjing University of Chinese MedicineNanjing 210023China

Two new 2-carboxymethyl-3-hexyl-maleic anhydride derivatives,arthrianhydride A(1)and B(2),along with three known compounds 3-5,were isolated from the fermentation broth of a grasshopper-associated fungus Arthrinium sp.NF2410.The structures of new compounds 1 and 2 were determined based on the analysis of the HR-ESI-MS and NMR spectroscopic data.Furthermore,compounds 1 and 2 were evaluated on inhibitory activity against the enzyme SHP2 and both of them showed moderate inhibitory activity against SHP2.

关键词： Grasshopper-associated fungi Secondary metabolites Structure elucidation SHP2 Inhibitory activity

Celastrol targets adenylyl cyclase-associated protein 1 to reduce macrophages-mediated inflammation and ameliorates high fat diet-induced metabolic syndrome in mice

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Acta Pharmaceutica Sinica B 2021年第5期11卷 1200-1212页

作者： Yuyu Zhu Ning Wan Xinni Shan Guoliang Deng Qiang Xu Hui Ye Yang Sun state key laboratory of pharmaceutical biotechnology Department of Biotechnology and Pharmaceutical SciencesSchool of Life SciencesNanjing UniversityNanjing 210023China Jiangsu Provincial key laboratory of Drug Metabolism and Pharmacokinetics State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 210009China Chemistry and Biomedicine Innovation Center(ChemBIC) Nanjing UniversityNanjing 210023China

Metabolic syndrome is a clustering of metabolic disorder with unclear molecular mechanism.Increasing studies have found that the pathogenesis and progression of metabolic syndrome are closely related to inflammation.Here,we report celastrol,a traditional Chinese medicine,can improve high fat diet-induced metabolic syndrome through suppressing resistin-induced inflammation.Mechanistically,celastrol binds to adenylyl cyclase associated protein 1(CAP1)and inhibits the interaction between CAP1 and resistin,which restrains the cyclic adenylate monophosphate(cAMP)-protein kinase A(PKA)-nuclear factor kappa-B(NF-kB)signaling pathway and ameliorates high fat diet-induced murine metabolic syndrome.Knockdown of CAP1 in macrophages abrogated the resistin-mediated inflammatory activity.In contrast,overexpression of CAP1 in macrophages aggravated inflammation.Taken together,our study identifies celastrol,which directly targets CAP1 in macrophages,might be a promising drug candidate for the treatment of inflammatory metabolic diseases,such as metabolic syndrome.

关键词： Metabolic syndrome Celastrol CAP1 Resistin Inflammation

Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma

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Acta Pharmaceutica Sinica B 2022年第2期12卷 558-580页

作者： Danyu Du Chan Liu Mengyao Qin Xiao Zhang Tao Xi Shengtao Yuan Haiping Hao Jing Xiong department of Pharmacology School of PharmacyChina Pharmaceutical UniversityNanjing 210009China Research Center of biotechnology School of Life Science and TechnologyChina Pharmaceutical UniversityNanjing 210009China Jiangsu key laboratory of Drug Screening China Pharmaceutical UniversityNanjing 210009China state key laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210009China key laboratory of Drug Metabolism and Pharmacokinetics China Pharmaceutical UniversityNanjing 210009China

Hepatocellular carcinoma(HCC)is an aggressive human cancer with increasing incidence worldwide.Multiple efforts have been made to explore pharmaceutical therapies to treat HCC,such as targeted tyrosine kinase inhibitors,immune based therapies and combination of chemotherapy.However,limitations exist in current strategies including chemoresistance for instance.Tumor initiation and progression is driven by reprogramming of metabolism,in particular during HCC development.Recently,metabolic associated fatty liver disease(MAFLD),a reappraisal of new nomenclature for nonalcoholic fatty liver disease(NAFLD),indicates growing appreciation of metabolism in the pathogenesis of liver disease,including HCC,thereby suggesting new strategies by targeting abnormal metabolism for HCC treatment.In this review,we introduce directions by highlighting the metabolic targets in glucose,fatty acid,amino acid and glutamine metabolism,which are suitable for HCC pharmaceutical intervention.We also summarize and discuss current pharmaceutical agents and studies targeting deregulated metabolism during HCC treatment.Furthermore,opportunities and challenges in the discovery and development of HCC therapy targeting metabolism are discussed.

关键词： Metabolic dysregulation Hepatocellular carcinoma Glycolysis Tricarboxylic acid cycle Pentose phosphate pathway Fatty acidβ-oxidation Glutamine metabolism Cancer therapy

SHP2 inhibition triggers anti-tumor immunity and synergizes with PD-1 blockade

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Acta Pharmaceutica Sinica B 2019年第2期9卷 304-315页

作者： Mingxia Zhao Wenjie Guo Yuanyuan Wu Chenxi Yang Liang Zhong Guoliang Deng Yuyu Zhu Wen Liu Yanhong Gu Yin Lu Lingdong Kong Xiangbao Meng Qiang Xu Yang Sun state key laboratory of pharmaceutical biotechnology Deparment of Biotechnology and Pharmaceutical Sciences School of Life Sciences Nanjing University Jiangsu key laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica School of Pharmacy Nanjing University of Chinese Medicine state key laboratory of Natural and Biomimetic Drugs Department of Chemical Biology School of Pharmaceutical Sciences Peking University department of Oncology the First Affiliated Hospital with Nanjing Medical University

Tyrosine phosphatase SHP2 is a promising drug target in cancer immunotherapy due to its bidirectional role in both tumor growth promotion and T-cell inactivation. Its allosteric inhibitor SHP099 is known to inhibit cancer cell growth both in vitro and in vivo. However, whether SHP099-mediated SHP2 inhibition retards tumor growth in vivo via anti-tumor immunity remains elusive. To address this, a CT-26 colon cancer xenograft model was established in mice since this cell line is insensitive to SHP099.Consequently, SHP099 minimally affected CT-26 tumor growth in immuno-deficient nude mice, but significantly decreased the tumor burden in CT-26 tumor-bearing mice with intact immune system.SHP099 augmented anti-tumor immunity, as shown by the elevated proportion of CD8tIFN-γtT cells and the upregulation of cytotoxic T-cell related genes including Granzyme B andPerforin, which decreased the tumor load. In addition, tumor growth in mice with SHP2-deficient T-cells was markedly slowed down because of enhanced anti-tumor responses. Finally, the combination of SHP099 and antiPD-1 antibody showed a higher therapeutic efficacy than either monotherapy in controlling tumor growthin two colon cancer xenograft models, indicating that these agents complement each other. Our study suggests that SHP2 inhibitor SHP099 is a promising candidate drug for cancer immunotherapy.

关键词： Cancer immunotherapy SHP2 SHP099 PD-1 Colon cancer

Increased complexity of gene structure and base composition in vertebrates

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Journal of Genetics and Genomics 2011年第7期38卷 297-305页

作者： Ying Wu Huizhong Yuan Shengjun Tan Jian-Qun Chen Dacheng Tian Haiwang Yang state key laboratory of pharmaceutical biotechnology Department of Biology Nanjing University Nanjing 210093 China

How the structure and base composition of genes changed with the evolution of vertebrates remains a puzzling question. Here we analyzed 895 orthologous protein-coding genes in six multicellular animals： human, chicken, zebrafish, sea squirt, fruit fly, and worm. Our analyses reveal that many gene regions, particularly intron and 3~ UTR, gradually expanded throughout the evolution of vertebrates from their invertebrate ancestors, and that the number of exons per gene increased. Studies based on all protein-coding genes in each genome provide consistent results. We also find that GC-content increased in many gene regions （especially 5＇ UTR） in the evolution of endotherms, except in coding-exons. Analysis of individual genomes shows that 3t UTR demonstrated stronger length and GC-content correlation with intron than 5~ UTR, and gene with large intron in all six species demonstrated relatively similar GC-content. Our data indicates a great increase in complexity in vertebrate genes and we propose that the requirement for morphological and functional changes is probably the driving force behind the evolution of structure and base composition complexity in multicellular animal genes.

关键词： GC-content Gene structure Intron UTR Vertebrate Endotherm

Loss of hnRNP A1 in murine skeletal muscle exacerbates high-fat diet-induced onset of insulin resistance and hepatic steatosis

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Journal of Molecular Cell Biology 2020年第4期12卷 277-290页

作者： Mingxia Zhao Lihong Shen Zijun Ouyang Manru Li Guoliang Deng Chenxi Yang Wei Zheng Lingdong Kong Xuefeng Wu Xudong Wu Wenjie Guo Ye Yin Qiang Xu Yang Sun state key laboratory of pharmaceutical biotechnology Department of Biotechnology and Pharmaceutical SciencesSchool of Life SciencesNanjing UniversityNanjing 210023China key laboratory of Human Functional Genomics of Jiangsu Province Department of Biochemistry and Molecular BiologyNanjing Medical UniversityNanjing 210029China state key laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China

Impairment of glucose(Glu)uptake and storage by skeletal muscle is a prime risk factor for the development of metabolic diseases.Heterogeneous nuclear ribonucleoprotein A1(hnRNP Al)is a highly abundant RNA-binding protein that has been implicated in diverse cellular functions.The aim of this study was to investigate the function of hnRNP A1 on muscle tissue insulin sensitivity and systemic Glu homeostasis.Our results showed that conditional deletion of hnRNP Al in the muscle gave rise to a severe insulin resistance phenotype in mice fed a high-fat diet(HFD).Conditional knockout mice fed a HFD showed exacerbated obesity,insulin resistance,and hepatic steatosis.In vitro interference of hnRNP Al in C2C12 myotubes impaired insulin signal transduction and inhibited Glu uptake,whereas hnRNP Al overexpression in C2C12 myotubes protected against insulin resistance induced by supraphysiological concentrations of insulin.The expression and stability of glycogen synthase(gysl)mRNA were also decreased in the absence of hnRNP A l.Mechanistically,hnRNP Al interacted with gys l and stabilized its mRNA,thereby promoting glycogen synthesis and maintaining the insulin sensitivity in muscle tissue.Taken together,our findings are the first to show that reduced expression of hnRNP Al in skeletal muscle affects the metabolic properties and systemic insulin sensitivity by inhibiting glycogen synthesis.

关键词： hnRNP A1 insulin resistance hepatic steatosis glycogen synthesis

Central functions of the orexinergic system

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Neuroscience Bulletin 2013年第3期29卷 355-365页

作者： Xiao-Yang Zhang Lei Yu Qian-Xing Zhuang Jing-Ning Zhu Jian-Jun Wang department of Biological Science and Technology and state key laboratory of pharmaceutical biotechnology School of Life Sciences Nanjing University

The neuropeptide orexin is synthesized by neurons exclusively located in the hypothalamus. However, these neurons send axons over virtually the entire brain and spinal cord and therefore constitute a unique central orexinergic system. It is well known that central orexin plays a crucial role in the regulation of various basic non-somatic and somatic physiological functions, including feeding, energy homeostasis, the sleep/wake cycle, reward, addiction, and neuroendocrine, as well as motor control. Moreover, the absence of orexin results in narcolepsy-cataplexy, a simultaneous somatic and non-somatic dysfunction. In this review, we summarize these central functions of the orexinergic system and associated diseases, and suggest that this system may hold a key position in somatic-non-somatic integration.

关键词： orexin sleep/wake cycle motor control narcolepsy-cataplexy integration of somatic-non-somaticresponses

Orexin Directly Enhances the Excitability of Globus Pallidus Internus Neurons in Rat by Co-activating OX1 and OX2 Receptors

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Neuroscience Bulletin 2017年第4期33卷 365-372页

作者： He-Ren Gao Qian-Xing Zhuang Yong-Xiao Zhang Zhang-Peng Chen Bin Li Xiao-Yang Zhang Yi-Ting Zhong Jian-Jun Wang Jing-Ning Zhu state key laboratory of pharmaceutical biotechnology and department of Biological Science and Technology School ofLife SciencesNanjing UniversityNanjing 210023China

Orexin, released from the hypothalamus, has been implicated in various basic non-somatic functions including feeding, the sleep-wakefulness cycle, emotion,and cognition. However, the role of orexin in somatic motor control is still little known. Here, using whole-cell patch clamp recording and immunostaining, we investigated the effect and the underlying receptor mechanism of orexin-A on neurons in the globus pallidus internus（GPi）,a critical structure in the basal ganglia and an effective target for deep brain stimulation therapy. Our results showed that orexin-A induced direct postsynaptic excitation of GPi neurons in a concentration-dependent manner.The orexin-A-induced excitation was mediated via co-activation of both OX1 and OX2 receptors. Furthermore, the immunostaining results showed that OX1 and OX2 receptors were co-localized in the same GPi neurons. These results suggest that the central orexinergic system actively modulates the motor functions of the basal ganglia via direct innervation on GPi neurons and presumably participates in somatic-non-somatic integration.

关键词： Orexin OX1 receptor OX2 receptor Globus pallidus internus Basal ganglia