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Strategies to overcome drug resistance using SHP2 inhibitors

Acta Pharmaceutica Sinica B 2021年第12期11卷 3908-3924页

作者： Meng Liu Shan Gao Reham M.Elhassan xuben hou Hao Fang School of Pharmaceutical Sciences Cheeloo College of MedicineShandong UniversityJinan 250012China

Encoded by PTPN11,the SHP2(Src homology-2 domain-containing protein tyrosine phosphatase-2)is widely recognized as a carcinogenic *** a promising anti-cancer drug target,SHP2 regulates many signaling pathways such as RAS-RAF-ERK,PI3 K-AKT and ***,SHP2 plays a significant role in regulating immune cell function in the tumor ***,five SHP2 allosteric inhibitors have been recruited in clinical studies for the treatment of *** recently,studies have proved the therapeutic potential of SHP2 inhibitor in overcoming drug resistance of kinase inhibitors and programmed cell death-1(PD-1)***,we review the structure,function and small molecular inhibitors of SHP2,and highlight recent progress in overcoming drug resistance using SHP2 *** hope this review would facilitate the future clinical development of SHP2 inhibitors.

关键词： SHP2 inhibitor Allosteric inhibitor Anti-cancer Drug resistance

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Targeting histone deacetylases for cancer therapy: Trends and challenges

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Acta Pharmaceutica Sinica B 2023年第6期13卷 2425-2463页

作者： Tao Liang Fengli Wang Reham M.Elhassan Yongmei Cheng Xiaolei Tang Wengang Chen Hao Fang xuben hou Department of Pharmacy the Second Hospital Affiliated Wannan Medical CollegeWuhu 241000China Department of Science and Education Translational Medicine Center&Vascular Disease Research Centerthe Second Hospital Affiliated Wannan Medical CollegeWuhu 241000China Clinical Pathogens Detection Engineering Center of Wuhu Wuhu 241000China Department of Medicinal Chemistry and Key Laboratory of Chemical Biology(Ministry of Education) School of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China

Dysregulation of histone deacetylases(HDACs) is closely related to tumor development and progression. As promising anticancer targets, HDACs have gained a great deal of research interests and two decades of effort has led to the approval of five HDAC inhibitors(HDACis). However, currently traditional HDACis, although effective in approved indications, exhibit severe off-target toxicities and low sensitivities against solid tumors, which have urged the development of next-generation of HDACi. This review investigates the biological functions of HDACs, the roles of HDACs in oncogenesis, the structural features of different HDAC isoforms, isoform-selective inhibitors, combination therapies, multitarget agents and HDAC PROTACs. We hope these data could inspire readers with new ideas to develop novel HDACi with good isoform selectivity, efficient anticancer effect, attenuated adverse effect and reduced drug resistance.

关键词： HDACs Oncogenesis Selective inhibitor Combination therapy Multitarget agent PROTAC

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New techniques and strategies in drug discovery

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Chinese Chemical Letters 2020年第7期31卷 1695-1708页

作者： Jintong Du Jing Guo Dongwei Kang Zhihong Li Guan Wang Jianbing Wu Zhen Zhang Hao Fang xuben hou Zhangjian Huang Guobo Li Xiaoyun Lu Xinyong Liu Liang Ouyang Li Rao Peng Zhan Xiaojin Zhang Yihua Zhang Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical SciencesJi'nan 250117China School of Pharmacy Ji'nan UniversityGuangzhou 510632China Department of Medicinal Chemistry Key Laboratory of Chemical Biology(Ministry of Education)School of Pharmaceutical SciencesShandong UniversityJi'nan 250012China Department of Chemistry Jiangsu Key Laboratory of Drug Design and OptimizationChina Pharmaceutical UniversityNanjing 211198China Stare Key Laboratory of Biotherapy and Cancer Center West China Hospitaland Collaborative Innovation Center of BiotherapySichuan UniversityChengdu 610041China Stare Key Laboratory of Natural Medicines Jiangsu Key Laboratory of Drug Discovery for Metabolic DiseasesChina Pharmaceutical UniversityNanjing 210009China Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education West China School of PharmacySichuan UniversityChengdu 610041China Key Laboratory of Pesticide&Chemical Biology(CCNU) Ministry of EducationDepartment of ChemistryCentral China Normal UniversityWuhan 430079China

Great success has been witnessed in last decades,some new techniques and strategies have been widely used in drug *** this roadmap,several representative techniques and strategies are highlighted to show recent advances in this filed.(A)A DOX protocol has been developed for accurate protein-ligand binding structure prediction,in which first principle method was used to rank the binding *** against crystal structures have found that DOX prediction achieved an impressive success rate of 99%,indicating significant improvement over molecular docking method.(B)Virtual target profiling is a compound-centric strategy enabling a parallel implementation of interrogating compounds against various targets in a single screen,which has been used in hit/lead identification,drug repositioning,and mechanism-of-action *** and emerging methods for virtual target profiling are briefly summarized herein.(C)Research on targeted autophagy to treat diseases has received encouraging ***,due to the complexity of autophagy and disease,experimental and in silico methods should be performed synergistically for the entire *** part focuses on in silico methods in autophagy research to promote their use in medicinal research.(D)Histone deacetylases(HDACs)play important roles in various biological functions through the deacetylation of lysine *** studies demonstrated that HDACs,which possess low deacetylase activities,exhibited more efficient defatty-acylase ***,we review the defatty-acylase activity of HDACs and describe examples for the design of isoform selective HDAC inhibitor.(E)The FDA approval of three kinase allosteric inhibitors and some others entering clinical study has spurred considerable interests in this targeted drug discovery area.(F)Recent advances are reviewed in structure-based design of novel antiviral agents to combat drug resistance.(G)Since nitric oxide(NO)exerts anticancer activity depending on

关键词： Protein-ligand binding structure Target profiling In silico autophagy method Defatty-acylase Allosteric kinase inhibitor Drug resistance Nitric oxide donor Photoactivation strategies

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HBV Inhibits LPS-induced NLRP3 Inflammasome Activation and IL-1β Production via Suppressing NF-κB Pathway and ROS Production

HBV Inhibits LPS-induced NLRP3 Inflammasome Activation and I...

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第十二届全国免疫学学术大会

作者： Zhang Cai Yu Xin hou xuben Han Qiuju Zhang Jian Tian Zhigang Institute of Immunopharmacology and Immunotherapy School of Pharmaceutical SciencesShandong University Institute of Immunology School of Life SciencesUniversity of Science and Technology of China

Background&Aims:Hepatitis B virus(HBV)developed multifaceted strategies to evade the surveillance of immune responses,while the precise mechanisms involved remain *** NLRP3 inflammasome plays crucial roles in ant-ivir... 详细信息

关键词： HBV HBeAg NLRP3 inflammasome IL-1β

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HBV Inhibits LPS-induced NLRP3 Inflammasome Activation and IL-1β Production via Suppressing NF-κB Pathway and ROS Production

HBV Inhibits LPS-induced NLRP3 Inflammasome Activation and I...

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第十三届全国免疫学学术大会

作者： Xin Yu Peixiang Lan xuben hou Qiuju Han Nan Lu Tao Li Chenwei Jiao Jian Zhang Cai Zhang Zhigang Tian Institute of Immunopharmacology and Immunotherapy School of Pharmaceutical SciencesShandong University Department of Medicinal Chemistry Key Laboratory of Chemical Biology of Natural Products (MOE)School of Pharmaceutical SciencesShandong University Institute of Diagnostics School of MedicineShandong University Division of Liver Diseases Shandong Provincial Hospital Department of Pediatric Surgery Shandong Provincial Hospital Institute of Immunology School of Life SciencesUniversity of Science and Technology of China

Background & Aims: Hepatitis B virus(HBV) developed multifaceted strategies to evade the surveillance of immune responses, while the precise mechanisms involved remain unclear. The NLRP3 inflammasome plays crucial roles in antiviral host defense and its downstream factor IL-1β has been shown to inhibit HBV infection in vivo. The study aims to assess whether HBV can affect the NLRP3 inflammasome signaling pathways and shed light on the underlying mechanisms HBV utilizes to evade host innate immune ***: The ability of HBV to inhibit LPS-induced NLRP3 inflammasome activation was evaluated by Western blot, quantitative RT-PCR, flow cytometry and ***: Kupffer cells expressed considerable amounts of NLRP3 and IL-1β after lipopolysaccharide(LPS) stimulation;whereas, chronic HBV infection suppressed LPS-induced NLRP3 and pro-IL-1β expression as well as IL-1β maturation. This inhibitory activity is mediated by HBeAg, and is involved in the inhibition of NF-κB signal pathway and reactive oxygen species(ROS) production. The inhibitory effect of HBeAg was confirmed in patients with chronic hepatitis B(CHB) and hepatocellular carcinoma by comparing the levels of IL-1β and NLRP3-related proteins in para-carcinoma tissues from HBeAg-positive or negative patients. Moreover, chronic HBV infection increases the susceptibility of mice to S. Typhimurium infection, possibly via inhibiting the NLRP3 inflammasome activation and IL-1β ***: HBeAg inhibits LPS-induced NLRP3 inflammasome activation and IL-1β production via suppressing NF-κB pathway and ROS production. This finding provides a novel mechanism of HBV-mediated suppression of innate immune responses and identifies new therapeutic targets for chronic HBV infection and related diseases.

关键词： HBV HBeAg NLRP3 inflammasome IL-1β

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鼠伤寒沙门氏菌Ⅲ型分泌系统抗感染类抑制剂的筛选

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微生物学通报 2023年第5期50卷 2099-2112页

作者：徐京华焦绪瑶侯旭奔高翔山东大学微生物技术研究院山东青岛266000 山东大学药学院山东济南250000

【背景】肠道沙门氏菌(Salmonella enterica)是一种常见的食源性肠道致病菌,可以感染人畜并引发食物中毒、伤寒等疾病。近年来因抗生素滥用导致肠道沙门氏菌耐药性问题日益严峻,迫切需要开发新型抗感染药物。肠道沙门氏菌致病的关键在... 详细信息

【背景】肠道沙门氏菌(Salmonella enterica)是一种常见的食源性肠道致病菌,可以感染人畜并引发食物中毒、伤寒等疾病。近年来因抗生素滥用导致肠道沙门氏菌耐药性问题日益严峻,迫切需要开发新型抗感染药物。肠道沙门氏菌致病的关键在于与宿主细胞接触后可以通过Ⅲ型分泌系统(typeⅢsecretion system,T3SS)向宿主细胞内注射效应蛋白,进而调控宿主细胞囊泡运输和免疫应答等生理活动,以方便其高效侵染宿主细胞。T3SS是一类由超过20种蛋白质组成、高度复杂的跨膜分子机器,是革兰氏阴性病原菌中普遍存在的一类蛋白质运输系统和毒力系统。在不同病原菌中,其结构与功能非常保守。位于T3SS核心跨膜区的SctV家族蛋白是T3SS中最保守的组分之一,参与T3SS能量供应和效应蛋白的分泌过程,SctV蛋白的关键氨基酸突变失活后会导致鼠伤寒沙门氏菌丧失对宿主的入侵能力。【目的】以沙门氏菌SctV家族蛋白为靶点,尝试通过虚拟筛选技术筛选与SctV胞内区相互作用的抗感染类T3SS抑制剂。【方法】结合体外相互作用分析、细菌生长曲线实验、细菌分泌实验和细胞侵染实验等对候选分子进行抑制效果的分析和验证。【结果】最终筛选出小分子抑制剂C4(纽莫康定B0)和C5(茜草素),二者均可以显著抑制T3SS分泌效应蛋白,并进一步抑制鼠伤寒沙门氏菌对NCM460细胞的侵染。进一步的研究发现,化合物C4和C5并不是通过结合到SctV胞内区而是通过其他不同机制来抑制细菌的毒性。【结论】化合物C4通过未知通路调控T3SS效应蛋白的分泌过程,而C5可能通过下调调控基因hilD的表达来抑制T3SS分泌效应蛋白,并进一步抑制沙门氏菌对NCM460细胞的侵染。本研究为针对T3SS开发新型抗感染药物提供了新的靶点和思路,并为后续T3SS抗感染类抑制剂的优化和改造提供了分子理论基础。

关键词：鼠伤寒沙门氏菌 Ⅲ型分泌系统 SctV蛋白抗感染类抑制剂

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