European Journal of Medicinal Chemistry最新文献

Design, synthesis and anti-tumor evaluation of novel pyrimidine and quinazoline analogues 新型嘧啶和喹唑啉类似物的设计、合成和抗肿瘤评价

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-11-18 DOI: 10.1016/j.ejmech.2024.117057

Ren-Jie Lin, Lin Xie, Tian-Yu Gao, Yi-Zhou Yang, Lan Huang, Kui Cheng, Zhi-Peng Chen

引用次数: 0

Optimization of SHP2 Allosteric Inhibitors with Novel Tail Heterocycles and Their Potential as Antitumor Therapeutics 优化具有新型尾部杂环的 SHP2 异源抑制剂及其作为抗肿瘤治疗药物的潜力

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-11-18 DOI: 10.1016/j.ejmech.2024.117078

Chengchun Zhu, Leilei Li, Yan Yu, Xiao Wang, Ying Shi, Yiping Gao, Kai Chen, Xiaoyu Liu, Yuqian Cui, Tao Zhang, Zhiyi Yu

{"title":"Optimization of SHP2 Allosteric Inhibitors with Novel Tail Heterocycles and Their Potential as Antitumor Therapeutics","authors":"Chengchun Zhu, Leilei Li, Yan Yu, Xiao Wang, Ying Shi, Yiping Gao, Kai Chen, Xiaoyu Liu, Yuqian Cui, Tao Zhang, Zhiyi Yu","doi":"10.1016/j.ejmech.2024.117078","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117078","url":null,"abstract":"SHP2, a non-receptor protein tyrosine phosphatase involved in cancers, plays a pivotal role in numerous cellular signaling cascades, including the MAPK and PD-L1/PD-1 pathways. Although several SHP2 allosteric inhibitors have already entered clinical trials, none have been approved to date. Therefore, the development of new SHP2 allosteric inhibitors with improved efficacy is urgently required. Herein, we report the optimization of tail heterocycles in SHP2 allosteric inhibitors using a structure-based drug design strategy. Four series of compounds with different tail skeletons were synthesized, among which D13 showed notable inhibitory activity (IC50 = 1.2 μM) against SHP2. Molecular docking and binding studies indicated that the newly synthesized compounds exerted enzymatic inhibitory effects by directly binding to SHP2 with relatively slow dissociation rates. At the cellular level, Huh7 cells demonstrated heightened sensitivity to the novel SHP2 inhibitors, and D13 exhibited superior antiproliferative activity (IC50 = 38 μM) by arresting G0/G1 cell cycle, facilitating cell apoptosis and suppressing the MAPK signaling pathway. In the in vivo study, D13 displayed significant antitumor activity in a Huh7 xenograft model and possessed favorable druggability with acceptable oral bioavailability (F = 54%) and half-life (t1/2 = 10.57 h). Collectively, this study lays a robust foundation for further optimization of the tail heterocycle skeleton in SHP2 allosteric inhibitors.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"18 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of a Highly Potent, N-terminal Domain-targeting degrader of AR-FL/AR-V7 for the treatment of Prostate Cancer 发现一种用于治疗前列腺癌的强效 N 端域靶向 AR-FL/AR-V7 降解剂

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-11-18 DOI: 10.1016/j.ejmech.2024.117079

Si Ha, Chenxuan Ji, Jiaqi Yang, Maoxu Xiao, Ziyi Xu, Wei-Wei Pan, Hua Xiang, Guoshun Luo

{"title":"Discovery of a Highly Potent, N-terminal Domain-targeting degrader of AR-FL/AR-V7 for the treatment of Prostate Cancer","authors":"Si Ha, Chenxuan Ji, Jiaqi Yang, Maoxu Xiao, Ziyi Xu, Wei-Wei Pan, Hua Xiang, Guoshun Luo","doi":"10.1016/j.ejmech.2024.117079","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117079","url":null,"abstract":"The clinical development of PROTACs targeting the androgen receptor (AR) for degradation has made significant progress. However, effective treatments for metastatic prostate cancers containing the androgen receptor splice variant 7 (AR-V7), a constitutively active mutant without the ligand-binding domain (LBD), are still lacking. Here, we reported the identification of a highly potent, noncovalent PROTAC targeting the N-terminal domain (NTD) of AR, NP18, which is developed from the covalent AR-NTD antagonist EPI-002, and effectively degrades both AR-FL and AR-V7 in 22Rv1 cells (DC50: 18 and 26 nM respectively). Mechanistically, NP18 interacts with the N-terminal domain (NTD) of both full-length AR (AR-FL) and splice variant 7 (AR-V7), leading to their selective and proteasomal degradation. Importantly, NP18 exhibited remarkably superior antitumor activity in both 22Rv1 xenograft and patient-derived xenograft (PDX) models than EPI-002. Taken together, these findings highlight NP18 as a promising candidate to counteract AR splice variant-driven resistance.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"248 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DNA or Not DNA —That is the Question Determining the Design of Platinum Anticancer Drugs DNA 与否--这是一个决定铂类抗癌药物设计的问题

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-11-17 DOI: 10.1016/j.ejmech.2024.117077

Suxing Jin, Chenyao Feng, Xiaoyong Wang

引用次数: 0

Discovery of a potent PARP1 PROTAC as a chemosensitizer for the treatment of colorectal cancer 发现强效 PARP1 PROTAC 作为治疗结直肠癌的化疗增敏剂

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-11-17 DOI: 10.1016/j.ejmech.2024.117062

Mingfei Wu, Yiming Jiang, Daoming Zhang, Yiquan Wu, Yuyuan Jin, Tao Liu, Xinfei Mao, Hengyuan Yu, Tengfei Xu, Yong Chen, Wenhai Huang, Jinxin Che, Bo Zhang, Tao Liu, Nengming Lin, Xiaowu Dong

{"title":"Discovery of a potent PARP1 PROTAC as a chemosensitizer for the treatment of colorectal cancer","authors":"Mingfei Wu, Yiming Jiang, Daoming Zhang, Yiquan Wu, Yuyuan Jin, Tao Liu, Xinfei Mao, Hengyuan Yu, Tengfei Xu, Yong Chen, Wenhai Huang, Jinxin Che, Bo Zhang, Tao Liu, Nengming Lin, Xiaowu Dong","doi":"10.1016/j.ejmech.2024.117062","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117062","url":null,"abstract":"Given the vulnerability of colorectal cancer (CRC) patients could not obtain a sustained benefit from chemotherapy, combination therapy is frequently employed as a treatment strategy. Targeting PARP1 blockade exhibit specific toxicity towards tumor cells with BRCA1 or BRCA2 mutations through synthetic lethality. This study focuses on developing a series of potent PROTACs targeting PARP1 in order to enhance the sensitivity of CRC cells with BRCA1 or BRCA2 mutations to chemotherapy. Compound C6, obtained based on precise structural optimization of the linker, has been shown to effectively degrade PARP1 with a DC50 value of 58.14 nM. Furthermore, C6 significantly increased the cytotoxic efficacy of SN-38, an active metabolite of Irinotecan, in BRCA-mutated CRC cells, achieving a favorable combination index (CI) of 0.487. In conclusion, this research underscores the potential benefits of employing a combination therapy that utilizes PAPRP1 degrader C6 alongside Irinotecan for CRC patients harboring BRCA mutations in CRC.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"34 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142645848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel potent SOS1 inhibitors containing a tricyclic quinazoline scaffold: a joint view of experiments and simulations 含有三环喹唑啉支架的新型强效 SOS1 抑制剂：实验与模拟的共同视角

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-11-17 DOI: 10.1016/j.ejmech.2024.117065

Luolong Qing, Zhengzai Cheng, Juan Xu, Ziwei Wang, Yuanyuan Li, Mario Gauthier, Silong Zhang, Huan He

引用次数: 0

Discovery of novel KSP-targeting PROTACs with potent antitumor effects in Vitro and in Vivo 发现新型 KSP 靶向 PROTACs，其体外和体内抗肿瘤效果显著

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-11-16 DOI: 10.1016/j.ejmech.2024.117052

Deng-Gao Zhao, JieYing Liu, Zhengxi Su, Wenbo Zou, Qianwei Zhou, Ting Yin, Tan Jiyao, Yan-Yan Ma

引用次数: 0

Promising Breakthroughs in Amyotrophic Lateral Sclerosis Treatment through Nanotechnology's Unexplored Frontier 通过纳米技术这一尚未开发的前沿领域，肌萎缩侧索硬化症的治疗有望取得突破性进展

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-11-16 DOI: 10.1016/j.ejmech.2024.117080

Soheil Sojdeh, Moein Safarkhani, Hossein Daneshgar, Abdullah Aldhaher, Golnaz Heidari, Ehsan Nazarzadeh Zare, Siavash Iravani, Ali Zarrabi, Navid Rabiee

{"title":"Promising Breakthroughs in Amyotrophic Lateral Sclerosis Treatment through Nanotechnology's Unexplored Frontier","authors":"Soheil Sojdeh, Moein Safarkhani, Hossein Daneshgar, Abdullah Aldhaher, Golnaz Heidari, Ehsan Nazarzadeh Zare, Siavash Iravani, Ali Zarrabi, Navid Rabiee","doi":"10.1016/j.ejmech.2024.117080","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117080","url":null,"abstract":"This article explores the transformative potential of nanotechnology in the treatment and diagnosis of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disorder characterized by motor neuron degeneration, muscle weakness, and eventual paralysis. Nanotechnology offers innovative solutions across various domains, including targeted drug delivery, neuroprotection, gene therapy and editing, biomarker detection, advanced imaging techniques, and tissue engineering. By enhancing the precision and efficacy of therapeutic interventions, nanotechnology facilitates key advancements such as crossing the blood-brain barrier, targeting specific cell types, achieving sustained therapeutic release, and enabling combination therapies tailored to the complex pathophysiology of ALS. Despite its immense promise, the clinical translation of these approaches faces challenges, including potential cytotoxicity, biocompatibility, and regulatory compliance, which must be addressed through rigorous research and testing. This review emphasizes the application of nanotechnology in targeted drug delivery and gene therapy/editing for ALS, drawing on the author’s prior work with various nanotechnological platforms to illustrate strategies for overcoming similar obstacles in drug and gene delivery. By bridging the gap between cutting-edge technology and clinical application, this article aims to highlight the vital role of nanotechnology in shaping the future of ALS treatment.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"249 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142645849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthesis, biological evaluation and mechanism study of a novel indole-pyridine chalcone derivative as antiproliferative agent against tumor cells through dual targeting tubulin and HK2 一种新型吲哚吡啶查尔酮衍生物的合成、生物学评价和机理研究：通过双重靶向小管蛋白和 HK2 抗肿瘤细胞增殖剂

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-11-16 DOI: 10.1016/j.ejmech.2024.117058

Mengzhu Zheng, Guangyuan Liu, Yawei Han, Pengyu Qian, Mingze Wu, Ming Xiang, Yirong Zhou

{"title":"Synthesis, biological evaluation and mechanism study of a novel indole-pyridine chalcone derivative as antiproliferative agent against tumor cells through dual targeting tubulin and HK2","authors":"Mengzhu Zheng, Guangyuan Liu, Yawei Han, Pengyu Qian, Mingze Wu, Ming Xiang, Yirong Zhou","doi":"10.1016/j.ejmech.2024.117058","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117058","url":null,"abstract":"Chalcones have the characteristics of simple structure, easy synthesis and potent anti-tumor activity. Herein, a small library of fifty-five novel indole-chalcone derivatives were rationally designed and facilely synthesized. Consequently, their antiproliferative activity was systematically evaluated. Among which, compound 26 exhibited the most potent antiproliferative activity, with IC50 value of 0.764 μM against MD-MBA-231 cells. Moreover, it displayed a 5-fold selectivity compared with normal human cells. Further investigation revealed that compound 26 bound at the colchicine binding site of tubulin, disrupted their fibrous structure, thereby blocking the progression of the cell cycle and inducing apoptosis. Molecular docking and cellular thermal shift assay (CETSA) experiments further demonstrated that compound 26 could specifically bind to hexokinase 2 (HK2) and inhibit its activity, leading to impaired mitochondrial function and hindered mitochondrial respiration. Based on the quantitative structure-activity relationship study, further structure modifications were performed. Employing biotin probe pull-down assays, we demonstrated that compound 26 exerted its antiproliferative activity through a dual targeting mechanism, which simultaneously disrupted microtubule function and inhibited HK2 activity. Taken together, these results highlighted that compound 26 might be a promising antiproliferative agent for human cancer therapy.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"37 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142642978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Nanomaterials exert biological effects by influencing the ubiquitin-proteasome system 纳米材料通过影响泛素-蛋白酶体系统发挥生物效应

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-11-15 DOI: 10.1016/j.ejmech.2024.116974

Zhen Ai, Dan Li, Shuquan Lan, Chao Zhang

引用次数: 0