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Development of small molecule extracellular signal-regulated kinases(ERKs) inhibitors for cancer therapy

Acta Pharmaceutica Sinica B 2022年第5期12卷 2171-2192页

作者： Xiaoli Pan Junping Pei Aoxue Wang Wen Shuai Lu Feng Faqian Bu Yumeng Zhu Lan Zhang Guan Wang Liang Ouyang State key laboratory of biotherapy and Cancer Center Innovation Center of Nursing ResearchNursing Key Laboratory of Sichuan ProvinceNational Clinical Research Center for GeriatricsWest China Hospitaland Collaborative Innovation Center of BiotherapySichuan UniversityChengdu 610041China Sichuan Engineering Research Center for Biomimetic Synthesis of Natural drugs School of Life Science and EngineeringSouthwest Jiaotong UniversityChengdu 610031China

The mitogen-activated protein kinase(MAPK)/extracellular signal-regulated kinase 1/2(ERK1/2) signaling pathway is widely activated by a variety of extracellular stimuli, and its dysregulation is associated with the proliferation, invasion, and migration of cancer cells. ERK1/2 is located at the distal end of this pathway and rarely undergoes mutations, making it an attractive target for anticancer drug development. Currently, an increasing number of ERK1/2 inhibitors have been designed and synthesized for antitumor therapy, among which representative compounds have entered clinical trials. When ERK1/2 signal transduction is eliminated, ERK5 may provide a bypass route to rescue proliferation, and weaken the potency of ERK1/2 inhibitors. Therefore, drug research targeting ERK5 or based on the compensatory mechanism of ERK5 for ERK1/2 opens up a new way for oncotherapy. This review provides an overview of the physiological and biological functions of ERKs, focuses on the structure-activity relationships of small molecule inhibitors targeting ERKs, with a view to providing guidance for future drug design and optimization, and discusses the potential therapeutic strategies to overcome drug resistance.

关键词： Mitogen-activated protein kinases Cancer Extracellular signalregulated kinase 1/2 inhibitors Extracellular signalregulated kinase 5 inhibitors Inhibition Selectivity

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Design,synthesis and antiproliferative activity of novel 2,7-disubstituted triazolo[1,5-a]pyrimidines

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Chinese Chemical Letters 2009年第10期20卷 1179-1182页

作者： Xin Zhai Nan Jiang Ke Liang Zhang Feng Bao Ping Gong key Lab of New drugs Design and Discovery of liaoning province School of Pharmaceutical Engineering Shenyang Pharmaceutical University Shenyang 110016 China liaoning Food and Drug Administration Technical Evaluation Center Shenyang 110003 China

In our efforts to identify novel potent anticancer agents, we synthesized a series of 2,7-disubstituted triazolo[1,5-a]pyrimidines （6-16）. Their antiproliferative activity against Bel-7402, HT- 1080 and WI-38 cell lines was tested by MTT assay in vitro. Four of the compounds （9-11 and 16） displayed promising antiproliferative activity superior to gefitinib, especially compound 9. A preliminary SAR study of these derivatives was performed.

关键词： Triazolo[1,5-a]pyrimidines Synthesis Antiproliferative activity

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Current trends and hotspots of depressive disorders with colorectal cancer:A bibliometric and visual study

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World Journal of Gastrointestinal Oncology 2024年第8期16卷 3687-3704页

作者： Zi-Wei Yan Ying-Nan Liu Qian Xu Yuan Yuan Tumor Etiology and Screening Department of Cancer Institute and General Surgery The First Hospital of China Medical UniversityShenyang 110001Liaoning ProvinceChina key laboratory of Cancer Etiology and Prevention in liaoning Education Department The First Hospital of China Medical UniversityShenyang 110001Liaoning ProvinceChina laboratory of GI Cancer Etiology and Prevention in liaoning province The First Hospital of China Medical UniversityShenyang 110001Liaoning ProvinceChina

BACKGROUND Depression is strongly associated with colorectal cancer(CRC).Few bibliometric analyses have systematically summarized the research focus and recent progress in this *** To determine the research status and hotspots by bibliometric analysis of relevant publications on the relationship between CRC and *** Articles on depression in CRC patients were collected from the Web of Science Core *** and VOSviewer software were used to visualize bibliometric *** From 2001 to 2022,Supportive Care in Cancer,the United States,Tilburg University,and Mols were the most productive and influential journal,country,institution,and author ***-occurrence cluster analysis of keywords placed quality of life,anxiety,and psychological stress in the center of the visual network *** clustering was performed for the clusters with studies of the relevant mechanism of action,which showed that:(1)Cytokines have a role essential for the occurrence and development of depressive disorders in CRC;(2)MicroRNAs have a role essential for the development of depressive disorders in CRC;(3)Some anticancer drugs have pro-depressant activity;and(4)Selective serotonin reuptake inhibitors have both antitumor and antidepressant *** Life quality and psychological nursing of the cancer population were key *** roles of cytokines and microRNAs,the pro-depression activity of anticancer drugs and their antitumor properties deserve in-depth study.

关键词： Depression Colorectal cancer Bibliometric analysis Cytokines drugs Mechanism

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CYS1 Promotes Peritoneal Metastasis via Inhibiting the Formation of E-cadherin/β-catenin Complex by Binding PHB2 in Gastric Cancer

CYS1 Promotes Peritoneal Metastasis via Inhibiting the Forma...

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2021年中国肿瘤标志物学术大会暨第十五届肿瘤标志物青年科学家论坛

作者： Hongfei Yan Xiaofang Che Yunpeng Liu Xiujuan Qu Department of Medical Oncology The First Hospital of China Medical University key laboratory of anticancer drugs and biotherapy of liaoning province The First Hospital of China Medical University liaoning province Clinical Research Center for Cancer the First Hospital of China Medical University key laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors Ministry of Education the First Hospital of China Medical University

Background: Peritoneum is the most common metastatic site in advanced gastric cancer(GC), which shortens the survival of GC patients and lacks effective treatment. It is of great significance for early diagnosis of peritoneal metastasis and looking for new treatment strategies that screening the key oncogenes in gastric cancer peritoneal metastasis and clarifying their novel ***: This study aims to explore the ability of prognostic prediction of CYS1 in GC and clarify the underlying mechanisms of CYS1 in facilitating peritoneal metastasis(PM) in ***: The Cancer Genome Atlas(TCGA) and Gene Expression Omnibus(GEO) databases were used to analyze PM-related genes and the association between CYS1 expression and prognosis in *** was performed to detect the expression of CYS1 in tumor and normal tissues of GC patients. Quantitative real-time polymerase chain reaction and western blots were applied to examine the expression of CYS1 in GC cell lines and expression of genes in downstream *** role of CYS1 on the adhesion between GC cells was explored with the hanging drop assay. The effect of CYS1 on the adhesion between GC cells and peritoneal mesothelial cells(PMC) was performed by the adhesion assay. The role of CYS1 on the migration and invasion of GC cell lines was investigated with the transwell assay. Mass spectrometry(MS) was used to detect the proteins binding with CYS1 in GC cells. GST-pull down assay was carried out to verify the binding motifs in vitro. Nuclear and cytosol fractionation assay and immunofluorescence assay exhibited the distribution of β-catenin. Orthotopic mouse model of GC demonstrated the effect of CYS1 on peritoneal metastasis of ***: 1. CYS1 is associated with peritoneal metastasis of GC. By using TCGA and GSE62254 datasets,we screened 804 genes related to poor prognosis in GC. Among them, by comparing genes in different metastatic sites, we finally found 59 genes whose expression was hig

关键词： CYS1 gastric cancer E-ca/β-catenin PHB2 peritoneal metastasis

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TRIM27 Is an Adverse Prognostic Biomarker and its Association with Immune and Molecular Profile in Right-sided Colon Cancer

TRIM27 Is an Adverse Prognostic Biomarker and its Associatio...

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2022CCTB中国肿瘤标志物学术大会暨中国整合肿瘤学大会暨第十六届肿瘤标志物青年科学家论坛暨中国肿瘤标志物产业创新大会

作者： Minghui Zhang Bowen Yang Lingyun Zhang Xiaoyu Guo Guangwei Zhang Xiaofang Che Ce Li Kezuo Hou Xiaojie Zhang Jinglei Qu Ti Wen Xiujuan Qu Department of Medical Oncology The First Hospital of China Medical University key laboratory of anticancer drugs and biotherapy of liaoning province The First Hospital of China Medical UniversityChina Liaoning Province Clinical Research Center for Cancer key laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors Ministry of Education Smart Hospital Management Department The First Hospital of China Medical University

Right-sided colon cancer(RCC),as an independent tumor entity,have a poor *** is imperative to find immune microenvironment-related genes for predicting RCC patients’ prognosis and explore their function in *** weighted gene coexpression network analysis(WGCNA),differentially expressed analysis,and univariate Cox analysis,we identified tripartite motif-containing 27(TRIM27) as a risk signature from The Cancer Genome Atlas(TCGA) and the Gene Expression Omnibus(GEO) *** predicted a poorer overall survival and increased lymph node metastasis,which were then validated in our 48 clinical *** immunohistochemistry(IHC),we found TRIM27 was highly expressed in both cancer cells and surrounding immunocytes,and its expression in tumor or immune cells both predicted a worse ***,the functional mechanism,immune and molecular characteristics of TRIM27 were explored using GSEA,Estimate,Cibersort,and GSVA at the single-cell,somatic mutation,and RNA-seq *** with TRIM27 high-expressed tumor cells presented lower CD4+ T cells infiltration and activation of the m TORC1/glycolysis *** addition,TRIM27 high patients were characterized by hypermetabolism,higher tumor purity,more BRAF mutation,and more chromosomal ***,TRIM27 is an important immune-related prognostic biomarker in RCC *** may function via activating m TORC1/glycolysis pathway and suppressing CD4+ T *** results suggest TRIM27 could be a promising therapeutic target in RCC.

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2-APQC,a small-molecule activator of Sirtuin-3(SIRT3),alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis

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Signal Transduction and Targeted Therapy 2024年第6期9卷 2748-2764页

作者： Fu Peng Minru Liao Wenke Jin Wei Liu Zixiang Li Zhichao Fan Ling Zou Siwei Chen Lingjuan Zhu Qian Zhao Gu Zhan Liang Ouyang Cheng Peng Bo Han Jin Zhang Leilei Fu West China School of Pharmacy and Department of biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China Sichuan Engineering Research Center for Biomimetic Synthesis of Natural drugs School of Life Science and EngineeringSouthwest Jiaotong UniversityChengdu 610031China State key laboratory of Southwestern Chinese Medicine Resources Hospital of Chengdu University of Traditional Chinese MedicineSchool of PharmacyChengdu University of Traditional Chinese MedicineChengdu 611137China School of Pharmaceutical Sciences Health Science CenterShenzhen UniversityShenzhen 518060China School of Traditional Chinese Materia Medica Key Laboratory of Structure-Based Drug Design&Discovery of Ministry of EducationShenyang Pharmaceutical UniversityShenyang 110016China

Sirtuin 3(SIRT3)is well known as a conserved nicotinamide adenine dinucleotide^(+)(NAD^(+))-dependent deacetylase located in the mitochondria that may regulate oxidative stress,catabolism and ATP *** evidence has recently revealed that SIRT3 plays its critical roles in cardiac fibrosis,myocardial fibrosis and even heart failure(HF),through its deacetylation ***,discovery of SIRT3 activators and elucidating their underlying mechanisms of HF should be urgently ***,we identified a new small-molecule activator of SIRT3(named 2-APQC)by the structure-based drug designing strategy.2-APQC was shown to alleviate isoproterenol(ISO)-induced cardiac hypertrophy and myocardial fibrosis in vitro and in vivo rat ***,in SIRT3 knockout mice,2-APQC could not relieve HF,suggesting that 2-APQC is dependent on SIRT3 for its protective ***,2-APQC was found to inhibit the mammalian target of rapamycin(mTOR)-p70 ribosomal protein S6 kinase(p70S6K),c-jun N-terminal kinase(JNK)and transforming growth factor-β(TGF-β)/small mother against decapentaplegic 3(Smad3)pathways to improve ISO-induced cardiac hypertrophy and myocardial *** upon RNA-seq analyses,we demonstrated that SIRT3-pyrroline-5-carboxylate reductase 1(PYCR1)axis was closely assoiated with *** activating PYCR1,2-APQC was shown to enhance mitochondrial proline metabolism,inhibited reactive oxygen species(ROS)-p38 mitogen activated protein kinase(p38MAPK)pathway and thereby protecting against ISO-induced mitochondrialoxidative ***,activation of SIRT3 by 2-APQC could facilitate AMP-activated protein kinase(AMPK)-Parkin axis to inhibit ISO-induced ***,our results demonstrate that 2-APQC is a targeted SIRT3 activator that alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis,which may provide a new clue on exploiting a promising drug candidate for the future HF therapeutics.

关键词： SIRT3 homeostasis metabolism

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Protein tyrosine phosphatases:emerging role in cancer therapy resistance

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Cancer Communications 2024年第6期44卷 637-653页

作者： Min Zhao Wen Shuai Zehao Su Ping Xu Aoxue Wang Qiu Sun Guan Wang Innovation Center of Nursing Research Nursing Key Laboratory of Sichuan ProvinceDepartment of BiotherapyCancer Center and State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalWest China School of NursingSichuan UniversityChengduSichuanP.R.China West China Biomedical Big Data Center Med-X Center for InformaticsSichuan UniversityChengduSichuanP.R.China Emergency Department Zigong Fourth People’s HospitalChengduSichuanP.R.China

Background:Tyrosine phosphorylation of intracellular proteins is a posttranslational modification that plays a regulatory role in signal transduction during cellular *** of signal transduction proteins caused by protein tyrosine phosphatases(PTPs)contributed their role as a convergent node to mediate cross-talk between signaling *** the context of cancer,PTP-mediated pathways have been identified as signaling hubs that enabled cancer cells to mitigate stress induced by clinical *** is achieved by the promotion of constitutive activation of growth-stimulatory signaling pathways or modulation of the immune-suppressive tumor *** evidences suggested that anticancer drugs will release their greatest therapeutic potency when combined with PTP inhibitors,reversing drug resistance that was responsible for clinical failures during cancer *** covered:This review aimed to elaborate recent insights that supported the involvement of PTP-mediated pathways in the development of resistance to targeted therapy and immune-checkpoint *** opinion:This review proposed the notion of PTP inhibition in anticancer combination therapy as a potential strategy in clinic to achieve long-term tumor *** clinical trials are currently underway to assess the safety and efficacy of combination therapy in advanced-stage tumors.

关键词： cancer treatment combination therapy drug resistance protein tyrosine phosphatase

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Natural Products and Derivatives Targeting at Cancer Energy Metabolism:A Potential Treatment Strategy

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Current Medical Science 2020年第2期40卷 205-217页

作者： Qi-qi WANGI Ming-xue LI Chen LI Xiao-xia GU Meng-zhu ZHENG Li-xia CHEN Hua LI Wuya College of Inovation School of Pharmaceutical EngineeringKey Laboratory of Structure-Based Drug Design&DiscoveryMinistry of EducationShenyang Pharmaceutical UniversiryShenyang 110016China Hubei key laboratory of Natural Medicinal Chemistry and Resource Evaluation School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China

In the 1920s,Dr Otto Warburg first suggested the significant difference in energy metabolism between malignant cancer cells and adjacent normal *** cells mainly adopt the glycolysis as energy source to maintain tumor cell growth and biosynthesis under aerobic *** on energy metabolism pathway in cancer cells has aroused the interest of cancer researchers all around the *** recent years,plentiful studics suggest that targeting the peculiar cancer energy metabolic pathways,including glycolysis,mitochondrial respiration,amino acid metabolism,and fatty acid oxidation may be an effective strategy to starve cancer cells by blocking essential *** products (NPs)are considered as the “treasure trove of small molecules drugs” and have played an extremely remarkable role in the discovery and development of anticancer *** numerous NPs have been reported to act on cancer energy metabolism ***,a comprehensive overview about cancer energy metabolism targets and their natural-occurring inhibitors is prepared.

关键词： cancer energy metabolism cancer therapy natural products binding targets,inhibitors

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CMAB009 plus irinotecan versus irinotecan-only as second-line treatment after fluoropyrimidine and oxaliplatin failure in KRAS wild-type metastatic colorectal cancer patients:promising findings from a prospective,open-label,randomized,phase III trial

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Cancer Communications 2019年第1期39卷 258-270页

作者： Yuankai Shi Jin Li Jianming Xu Yan Sun Liwei Wang Ying Cheng Wei Liu Guoping Sun Yigui Chen Li Bai Yiping Zhang Xiaohui He Yi Luo Zhehai Wang Yunpeng Liu Qiang Yao Yuhong Li Shukui Qin Xiaohua Hu Feng Bi Rongsheng Zheng Xuenong Ouyang Department of Medical Oncology Beijing Key Laboratory of Clinical Study On Anticancer Molecular Targeted DrugsNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021P.R.China Fudan University Shanghai Cancer Center Shanghai 200032P.R.China The Affiliated Hospital of Military Medical Sciences Beijing 100071P.R.China Shanghai General Hospital Shanghai 200080P.R.China Jilin Cancer Hospital Changchun 130012JilinP.R.China Tumor Hospital of Hebei province Shijiazhuang 050011HebeiP.R.China The First Affiliated Hospital of Anhui Medical University Hefei 230022AnhuiP.R.China Fujian Provincial Cancer Hospital Fuzhou 350014FujianP.R.China Chinese People’s Liberation Army General Hospital Beijing 100853P.R.China Zhejiang Cancer Hospital Hangzhou 310022ZhejiangP.R.China Hunan Cancer Hospital Changsha 410013HunanP.R.China Shandong Cancer Hospital Jinan 250117ShandongP.R.China The First Hospital of China Medical University Shenyang 110001LiaoningP.R.China Tianjin People’s Hospital Tianjin 300121P.R.China Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center of Cancer MedicineGuangzhou 510060GuangdongP.R.China Chinese People’s Liberation Army Bayi Hospital Nanjing 210002JiangsuP.R.China The Guangxi Zhuang Autonomous Region Tumor Hospital Nanning 530021GuangxiP.R.China West China Hospital Chengdu 610041SichuanP.R.China First Affiliated Hospital of Bengbu Medical College Bengbu 233004AnhuiP.R.China Fuzhou People’s Liberation Army General Hospital Fuzhou 350025FujianP.R.China

Background:The 5-fluorouracil/leucovorin plus oxaliplatin(FOLFOX)regimen is the standard first-line treatment for metastatic colorectal cancer(mCRC),however,the optimal second-line regimen for KRAS wild-type mCRC patients is still *** this study,we aimed to determine the clinical efficacy and safety of CMAB009 plus irinotecan compared to irinotecan-only as a second-line regimen for treating KRAS wild-type mCRC ***:Patients with KRAS wild-type mCRC who had previously failed to respond to FOLFOX treatment were ran-domly assigned in a 2:1 ratio,to receive CMAB009 plus irinotecan or *** receiving irinotecan-only were permitted to switch to CMAB009 therapy on disease progression and were grouped as the sequential-CMAB009 *** primary endpoints were overall response rate(ORR)and median progression-free survival(PFS).The second-ary endpoints were median overall survival(OS),disease control rate(DCR),clinical benefit rate(CBR),and duration of response(DOR).Results:The CMAB009 plus irinotecan arm demonstrated significantly improved ORR(33.2%vs.12.8%;P<0.001)and longer median PFS(169 days vs.95 days;P<0.001)as compared to the irinotecan-only *** receiv-ing CMAB009 plus irinotecan also demonstrated improved DCR(80.1%vs.65.2%,P<0.001),CBR(30.0%vs.14.6%,P<0.001),and DOR(210 days vs.109 days;P<0.001)as compared to ***,patients treated with CMAB009 had an increased risk of skin rash(66.9%vs.5.5%,P<0.001)and paronychia(9.8%vs.0.0%,P<0.001).Anti-drug antibodies(ADA)were detected in 3.6%of patients,and only 0.9%of patients who received CMAB009 experienced hypersensitivity *** patients receiving sequential-CMAB009 therapy after failure with irinotecan,their median PFS was 84 days (95% CI 65 to 113 days). The median OS was 425 days for patients receiving CMAB009 plus irinotecan and 401 days for those with sequential-CMAB009 (P = 0.940). Conclusions: Treatment with CMAB009 plus irinotecan was found

关键词： CMAB009 Cetuximab Irinotecan Second-line mCRC EGFR KRAS Immunogenicity Fluoropyrimidine Oxaliplatin failure

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Development of pharmacological immunoregulatory anticancer therapeutics:current mechanistic studies and clinical opportunities

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Signal Transduction and Targeted Therapy 2024年第6期9卷 2477-2526页

作者： Nanhao Yin Xintong Li Xuanwei Zhang Shaolong Xue Yu Cao Gabriele Niedermann You Lu Jianxin Xue Division of Thoracic Tumor Multimodality Treatment Cancer Center&State Key Laboratory of Biotherapyand The National Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityNo.37Guoxue LaneChengdu 610041 SichuanPR China Department of Gynecology and Obstetrics West China Second University HospitalSichuan UniversityNo.20Section 3South Renmin RoadChengdu 610041 SichuanPR China Department of Emergency Medicine Laboratory of Emergency MedicineWest China HospitalSichuan UniversityNo.37Guoxue LaneChengdu 610041 SichuanPR China Institute of Disaster Medicine&Institute of Emergency Medicine Sichuan UniversityNo.17Gaopeng AvenueChengdu 610041 SichuanPR China Department of Radiation Oncology Medical Center—University of FreiburgFaculty of MedicineUniversity of FreiburgGerman Cancer Consortium(DKTK)Partner Site DKTK-FreiburgRobert-Koch-Strasse 379106 FreiburgGermany laboratory of Clinical Cell Therapy West China HospitalSichuan UniversityNo.2222Xinchuan RoadChengdu 610041 SichuanPR China

Immunotherapy represented by anti-PD-(L)1 and anti-CTLA-4 inhibitors has revolutionized cancer treatment,but challenges related to resistance and toxicity still *** to the advancement of immuno-oncology,an increasing number of novel immunoregulatory targets and mechanisms are being revealed,with relevant therapies promising to improve clinical immunotherapy in the foreseeable ***,comprehending the larger picture is *** this review,we analyze and summarize the current landscape of preclinical and translational mechanistic research,drug development,and clinical trials that brought about next-generation pharmacological immunoregulatory anti-cancer agents and drug candidates beyond classical immune checkpoint *** with further clarification of cancer immunobiology and advances in antibody engineering,agents targeting additional inhibitory immune checkpoints,including LAG-3,TIM-3,TIGIT,CD47,and B7 family members are becoming an important part of cancer immunotherapy research and discovery,as are structurally and functionally optimized novel anti-PD-(L)1 and anti-CTLA-4 agents and agonists of co-stimulatory molecules of T *** by bispecific T cell engagers,newly emerging bi-specific and multi-specific antibodies targeting immunoregulatory molecules can provide considerable clinical ***-generation agents also include immune epigenetic drugs and cytokine-based *** therapies,cancer vaccines,and oncolytic viruses are not covered in this *** comprehensive review might aid in further development and the fastest possible clinical adoption of effective immuno-oncology modalities for the benefit of patients.

关键词： clinical immuno landscape

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