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Angiotensin-converting enzyme 2 as a potential therapeutic target for COVID-19:A review

Journal of Pharmaceutical Analysis 2022年第2期12卷 215-220页

作者： Bhagat Singh Dheer Singh Vinod Verma Ramakant Yadav Raj Kumar Department of Medical Laboratory Technology Faculty of Paramedical SciencesUttar Pradesh University of Medical SciencesEtawah206130India Department of Anaesthesiology and Critical Care Uttar Pradesh University of Medical SciencesEtawah206130India Stem Cell Research Centre Department of HematologySanjay Gandhi Post Graduate Institute of Medical SciencesLucknow226014India Department of Neurology Uttar Pradesh University of Medical SciencesEtawah206130India Department of Neurosurgery Uttar Pradesh University of Medical SciencesEtawah206130India

As of August 16,2021,there have been 207,173,086 confirmed cases and 4,361,996 deaths due to the coronavirus disease(COVID-19),and the pandemic remains a global challenge.To date,no effective and approved drugs are available for the treatment of COVID-19.Angiotensin-converting enzyme 2(ACE2)plays a crucial role in the invasion into host cells by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the etiological agent of COVID-19.Notably,ACE2 density is influenced by medical conditions,such as hypertension,or by drugs,including angiotensin-converting enzyme inhibitors(ACEIs)and angiotensin receptor blockers(ARBs),which can change the fate of SARS-CoV-2 infectivity.ACE2 is a target for these drugs and can be manipulated to limit the viral entry and replication within the cells.Different strategies aimed at blocking ACE2 with small molecules,peptides,and antibodies,or by neutralizing the virus through its competitive binding with human recombinant soluble ACE2(hrsACE2)are currently under investigation.In this article,we review the current state of knowledge that emphasizes the need to find effective therapeutic agents against COVID-19 by exploiting ACE2 as a potential target.The increased soluble ACE2 levels and the application of hrsACE2 in patients with COVID-19 can be implemented to control the disease.It has not yet been established whether hypertension and other comorbidities,independent of age,have a direct role in COVID-19.Therefore,the use of renin-angiotensin system inhibitors,ACEIs and ARBs,should not be discontinued during COVID-19 treatment.

关键词： COVID-19 ACE2 receptors hrsACE2 ACE inhibitors Ras AT1R blocker

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Targeting the“undruggable”cancer driver genes:Ras,myc,and tp53

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BIOCELL 2023年第7期47卷 1459-1472页

作者： XINGBO WU DAN PAN SHOUYI TANG YINGQIANG SHEN State Key Laboratory of Oral Diseases National Clinical Research Center for Oral DiseasesResearch Unit of Oral Carcinogenesis and ManagementChinese Academy of Medical SciencesWest China Hospital of StomatologySichuan UniversityChengdu610041China

The term“undruggable”is to describe molecules that are not targetable or at least hard to target pharmacologically.Unfortunately,some targets with potent oncogenic activity fall into this category,and currently little is known about how to solve this problem,which largely hampered drug research on human cancers.Ras,as one of the most common oncogenes,was previously considered“undruggable”,but in recent years,a few small molecules like SotoRasib(AMG-510)have emerged and proved their targeted anti-cancer effects.Further,myc,as one of the most studied oncogenes,and tp53,being the most common tumor suppressor genes,are both considered“undruggable”.Many attempts have been made to target these“undruggable”targets,but little progress has been made yet.This article summarizes the current progress of direct and indirect targeting approaches for Ras,myc,two oncogenes,and tp53,a tumor suppressor gene.These are potential therapeutic targets but are considered“undruggable”.We conclude with some emerging research approaches like proteolysis targeting chimeRas(PROTACs),cancer vaccines,and artificial intelligence(AI)-based drug discovery,which might provide new cues for cancer intervention.Therefore,this review sets out to clarify the current status of targeted anti-cancer drug research,and the insights gained from this review may be of assistance to learn from experience and find new ideas in developing new chemicals that directly target such“undruggable”molecules.

关键词： Ras Myc Tp53 Antineoplastic agents Pharmacology Oncogene proteins Antagonists and inhibitors

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KRas对T⁃ALL细胞株增殖及凋亡的影响

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中国实验血液学杂志 2022年第4期30卷 1040-1048页

作者：柳梓杨舒逸傅国苏虹宇朱丹曾腊梅马德禹邹琳重庆医科大学附属儿童医院临床分子医学中心国家儿童健康与疾病临床医学研究中心儿童发育疾病研究教育部重点实验室儿科学重庆市重点实验室重庆400014 上海交通大学附属儿童医院临床研究中心上海交通大学医学院儿童感染免疫与重症医学研究院上海200062

目的:探讨Ras蛋白家族在维持T⁃ALL细胞株体外生长中的功能。方法:纯化T⁃ALL细胞株DNA,利用PCR法扩增3个Ras基因(KRas、NRas、HRas)的编码区。经T⁃A克隆后,Sanger法对KRas、NRas、HRas基因编码区测序。将siRNA克隆到pSEH⁃361载体,在HEK⁃2... 详细信息

目的:探讨Ras蛋白家族在维持T⁃ALL细胞株体外生长中的功能。方法:纯化T⁃ALL细胞株DNA,利用PCR法扩增3个Ras基因(KRas、NRas、HRas)的编码区。经T⁃A克隆后,Sanger法对KRas、NRas、HRas基因编码区测序。将siRNA克隆到pSEH⁃361载体,在HEK⁃293T细胞中与pAMPHO和pVSVG一起包装成逆转录病毒,随后感染T⁃ALL细胞。qRT⁃PCR和Western blot检测基因表达情况。利用Annexin V⁃PE/7⁃AAD染色T⁃ALL细胞,流式细胞术检测细胞凋亡情况。利用Hoechst 33258染色T⁃ALL细胞,流式细胞术检测细胞周期分布情况。经抗体染色,荧光显微镜观察cleaved⁃Caspase 3蛋白的表达。结果:在T⁃ALL细胞株中,除Loucy和P12⁃ICH细胞KRas基因发生c.6187G>A(p.KRasG12D)突变,其余Ras基因均未发现错义突变。除PEER细胞(IC_(50)=47.916μmol/L)外,泛Ras抑制剂Compound 3144对其它T⁃ALL细胞均有一定杀伤作用。同样,除PEER细胞(IC_(50)=94.2265μmol/L)外,Tipifarnib可诱导多种T⁃ALL细胞凋亡。抑制KRas表达后,T⁃ALL细胞凋亡明显,细胞周期阻滞。结论:KRas蛋白维持T⁃ALL细胞株体外生长,是治疗T⁃ALL的潜在药物靶点。

关键词： Ras 急性T淋巴细胞白血病细胞增殖细胞凋亡

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Targeting Ras phosphorylation in cancer therapy:Mechanisms and modulators

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Acta Pharmaceutica Sinica B 2021年第11期11卷 3433-3446页

作者： Yuran Qiu Yuanhao Wang Zongtao Chai Duan Ni Xinyi Li Jun Pu Jie Chen Jian Zhang Shaoyong Lu Chuan Lv Mingfei Ji Department of Urology Changzheng HospitalNaval Military Medical UniversityShanghai 200003China Department of Pathophysiology Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of EducationShanghai Jiao Tong UniversitySchool of MedicineShanghai 200025China Department of Hepatic Surgery VI Eastern Hepatobiliary Surgery HospitalSecond Military Medical UniversityShanghai 200438China Department of Cardiology Renji HospitalShanghai Jiao Tong UniversitySchool of MedicineShanghai 200120China Department of Plastic Surgery Changhai HospitalNaval Military Medical UniversityShanghai 200438China

Ras,a member of the small GTPase family,functions as a binary switch by shifting between inactive GDP-loaded and active GTP-loaded state.Ras gain-of-function mutations are one of the leading causes in human oncogenesis,accounting for w19%of the global cancer burden.As a well-recognized target in malignancy,Ras has been intensively studied in the past decades.Despite the sustained efforts,many failures occurred in the earlier exploration and resulted in an‘undruggable’feature of Ras proteins.Phosphorylation at several residues has been recently determined as regulators for wild-type and mutated Ras proteins.Therefore,the development of Ras inhibitors directly targeting the Ras mutants or towards upstream regulatory kinases supplies a novel direction for tackling the anti-Ras difficulties.A better understanding of Ras phosphorylation can contribute to future therapeutic strategies.In this review,we comprehensively summarized the current advances in Ras phosphorylation and provided mechanistic insights into the signaling transduction of associated pathways.Importantly,the preclinical and clinical success in developing anti-Ras drugs targeting the upstream kinases and potential directions of harnessing allostery to target Ras phosphorylation sites were also discussed.

关键词： Ras Phosphorylation Undruggable Protein kinases Allostery

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Integrated genomic analyses identify high-risk factors and actionable targets in T-cell acute lymphoblastic leukemia

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Blood Science 2022年第1期4卷 16-28页

作者： Haichuan Zhu Bingjie Dong Yingchi Zhang Mei Wang Jianan Rao Bowen Cui Yu Liu Qian Jiang Weitao Wang Lu Yang Anqi Yu Zongru Li Chao Liu Leping Zhang Xiaojun Huang Xiaofan Zhu Hong Wu The MOE Key Laboratory of Cell Proliferation and Differentiation School of Life SciencesPeking UniversityBeijing 100871China Peking-Tsinghua Center for Life Sciences Peking UniversityBeijing 100871China State Key Laboratory of Experimental Hematology Institute of Hematology and Blood Diseases HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjin 300020China Pediatric Translational Medicine Institute Shanghai Children’s Medical CenterSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina Shanghai Key Laboratory of Clinical Molecular Diagnostics for Pediatrics ShanghaiChina Peking University Institute of Hematology National Clinical Research Center for Hematologic DiseaseBeijing 100044China Department of Pediatrics Peking University People’s HospitalBeijing 100044China Current address:Institute of Biology and Medicine College of Life and Health SciencesWuhan University of Science and TechnologyHubei 430081China

T cell acute lymphoblastic leukemia(T-ALL)is an aggressive hematologic malignancy often associated with poor outcomes.To identify high-risk factors and potential actionable targets for T-ALL,we perform integrated genomic and transcriptomic analyses on samples from 165 Chinese pediatric and adult T-ALL patients,of whom 85%have outcome information.The genomic mutation landscape of this Chinese cohort is very similar to the Western cohort published previously,except that the rate of NOTCH1 mutations is significant lower in the Chinese T-ALL patients.Among 47 recurrently mutated genes in 7 functional categories,we identify Ras pathway and PTEN mutations as poor survival factors for non-TAL and TAL subtypes,respectively.Mutations in the PI3K pathway are mutually exclusive with mutations in the Ras and NOTCH1 pathways as well as transcription factors.Further analysis demonstrates that approximately 43%of the high-risk patients harbor at least one potential actionable alteration identified in this study,and T-ALLs with Ras pathway mutations are hypersensitive to MEKi in vitro and in vivo.Thus,our integrated genomic analyses not only systematically identify high-risk factors but suggest that these high-risk factors are promising targets for T-ALL therapies.

关键词： High risk PI3K Ras T-ALL WES

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Different oncological features of colorectal cancer codon-specific KRas mutations:Not codon 13 but codon 12 have prognostic value

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World Journal of Gastroenterology 2023年第32期29卷 4883-4899页

作者： Hong-Min Ahn Duck-Woo Kim Tae Gyun Lee Hye-Rim Shin In Jun Yang Jeehye Lee Jung Wook Suh Heung-Kwon Oh Sung-Bum Kang Department of Surgery Seoul National University Bundang HospitalSeongnam 13620South Korea Department of Pathology Seoul National University Bundang HospitalSeongnam 13620South Korea Department of Pathology Seoul National University HospitalSeoul 03080South Korea

BACKGROUND Approximately 40%of colorectal cancer(CRC)cases are linked to Kirsten rat sarcoma viral oncogene homolog(KRas)mutations.KRas mutations are associated with poor CRC prognosis,especially KRas codon 12 mutation,which is associated with metastasis and poorer survival.However,the clinicopathological characteristics and prognosis of KRas codon 13 mutation in CRC remain unclear.AIM To evaluate the clinicopathological characteristics and prognostic value of codonspecific KRas mutations,especially in codon 13.METHODS This retrospective,single-center,observational cohort study included patients who underwent surgery for stage I-III CRC between January 2009 and December 2019.Patients with KRas mutation status confirmed by molecular pathology reports were included.The relationships between clinicopathological characteristics and individual codon-specific KRas mutations were analyzed.Survival data were analyzed to identify codon-specific KRas mutations as recurrence-related factors using the Cox proportional hazards regression model.RESULTS Among the 2203 patients,the incidence of KRas codons 12,13,and 61 mutations was 27.7%,9.1%,and 1.3%,respectively.Both KARS codons 12 and 13 mutations showed a tendency to be associated with clinical characteristics,but only codon 12 was associated with pathological features,such as stage of primary tumor(T stage),lymph node involvement(N stage),vascular invasion,perineural invasion,tumor size,and microsatellite instability.KRas codon 13 mutation showed no associations(77.2%vs 85.3%,P=0.159),whereas codon 12 was associated with a lower 5-year recurrence-free survival rate(78.9%vs 75.5%,P=0.025).In multivariable analysis,along with T and N stages and vascular and perineural invasion,only codon 12(hazard ratio:1.399;95%confidence interval:1.034-1.894;P=0.030)among KRas mutations was an independent risk factor for recurrence.CONCLUSION This study provides evidence that KRas codon 13 mutation is less likely to serve as a prognostic biomarker than codon 12 mutation for CRC in a large-

关键词： Genes Ras Codon Colonic neoplasms Rectal neoplasms

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Glycyrrhetinic acid binds to the conserved P-loop region and interferes with the interaction of Ras-effector proteins

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Acta Pharmaceutica Sinica B 2019年第2期9卷 294-303页

作者： Yuan Zhang Zhihua Wang Xiaoyao Ma Shengnan Yang Xueyan Hu Jin Tao Yuanyuan Houn Gang Bai State Key Laboratory of Medicinal Chemical Biology College of Pharmacy and Tianjin Key Laboratory of Molecular Drug ResearchNankai University

Members of the Ras proto-oncogene superfamily are indispensable molecular switches that play critical roles in cell proliferation, differentiation, and cell survival. Recent studies have attempted to prevent the interaction of Ras/GTP with Ras guanine nucleotide exchange factors(GEFs), impair Raseffector interactions, and suppress Ras localization to prevent oncogenic signalling. The present study aimed to investigate the effect of the natural triterpenoic acid inhibitor glycyrrhetinic acid, which is isolated from the roots of Glycyrrhiza plant species, on Ras stability. We found that glycyrrhetinic acid may bind to the P-loop of Ras and alter its stability. Based on our biochemical tests and structural analysis results, glycyrrhetinic acid induced a conformational change in Ras. Meanwhile, glycyrrhetinic acid abolishes the function of Ras by interfering with the effector protein RAF kinase activation and Ras/MAPK signalling.

关键词： Glycyrrhetinic acid Ras Allosteric inhibitor Ras/MAPK signalling

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以SOS1为靶标的抗肿瘤小分子调节剂研究进展

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中国新药杂志 2022年第11期31卷 1072-1079页

作者：范懿庆唐春雷范为正江南大学药学院无锡214122

SOS1(son of sevenless 1)是激活细胞中大鼠肉瘤(rat sarcoma,Ras)蛋白至关重要的鸟嘌呤核苷酸交换因子(guanine nucleotide exchange factors,GEF)。SOS1蛋白由多段结构域组成,这些结构域的功能与Ras及其下游信号通路的表达密切相关。... 详细信息

SOS1(son of sevenless 1)是激活细胞中大鼠肉瘤(rat sarcoma,Ras)蛋白至关重要的鸟嘌呤核苷酸交换因子(guanine nucleotide exchange factors,GEF)。SOS1蛋白由多段结构域组成,这些结构域的功能与Ras及其下游信号通路的表达密切相关。目前已经报道了大量的SOS1抑制剂与一定量的SOS1激动剂,这些分子大部分能有效抑制下游信号通路的表达。其中由德国勃林格英格翰公司研发的化合物BI-1701963(结构未公布)已进入Ⅰ期临床试验。虽然SOS1化合物的开发还不够成熟,但是该类小分子对于“不可成药”靶点Ras而言,是一种可行的替代策略。本文在查阅相关文献的基础上,对SOS1的结构域以及相关通路进行系统描述,并对目前已有的SOS1小分子调节剂的发展情况进行总结,为SOS1小分子调节剂的研发提供参考。

关键词： SOS1 Ras 信号通路抗肿瘤抑制剂激动剂

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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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^(18)F-FDG PET/CT影像组学预测非小细胞肺癌KRas基因突变的价值

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中华核医学与分子影像杂志 2023年第7期43卷 391-396页

作者：王婧伊黄威橙曹欣张寓祥杨卫东康飞汪静空军军医大学第一附属医院核医学科西安710032 西北大学信息科学与技术学院西安710127

目的评估基于^(18)F-FDG PET/CT的影像组学模型对非小细胞肺癌(NSCLC)患者Kirsten大鼠肉瘤病毒癌基因同源物(KRas)突变状态的预测效能。方法回顾性分析2016年1月至2021年1月在空军军医大学第一附属医院行^(18)F-FDG PET/CT、KRas基因检... 详细信息

目的评估基于^(18)F-FDG PET/CT的影像组学模型对非小细胞肺癌(NSCLC)患者Kirsten大鼠肉瘤病毒癌基因同源物(KRas)突变状态的预测效能。方法回顾性分析2016年1月至2021年1月在空军军医大学第一附属医院行^(18)F-FDG PET/CT、KRas基因检测的258例NSCLC患者(男180例、女78例,年龄33~91岁)资料。入组患者按7∶3的比例随机分为训练集(n=180)和验证集(n=78)。分别勾画PET和CT图像肿瘤病灶,提取PET与CT病灶影像组学特征。通过最小绝对收缩和选择算子(LASSO)筛选影像组学特征。建立CT影像组学评分(RS)模型、PET/CT RS模型及PET/CT RS与临床信息相结合的复合模型。绘制ROC曲线评估各模型的预测效能。结果CT RS模型共纳入4个影像组学特征;PET/CT RS模型共纳入4个CT影像组学特征及8个PET影像组学特征。CT RS模型和PET/CT RS模型在训练集、验证集中KRas突变型与野生型患者RS差异均有统计学意义(z值:-8.30~-4.10,均PRas基因突变中表现最佳,训练集和验证集AUC分别为0.879和0.852,高于CT RS模型(0.813和0.770)及PET/CT RS模型(0.858和0.834);准确性[81.67%(147/180)和79.49%(62/78)]也高于CT RS模型[75.00%(135/180)和74.36%(58/78)]及PET/CT RS模型[78.89%(142/180)和78.21%(61/78)]。结论基于影像组学特征的模型可预测KRas突变状态,PET/CT RS联合年龄的复合模型可提高预测效能。

关键词：癌非小细胞肺突变基因 Ras 正电子发射断层显像术体层摄影术 X线计算机氟脱氧葡萄糖F18 预测影像组学

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