European Journal of Medicinal Chemistry最新文献_第10页

Design, synthesis and biological evaluation of biaryl amide derivatives as modulators of multi-drug resistance 作为多重耐药性调节剂的双芳基酰胺衍生物的设计、合成和生物学评价

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-11-22 DOI: 10.1016/j.ejmech.2024.117090

Ying-Yuan Peng , Zhi-Xian Shi , Min Yu , Sami Karam , Zhi-Long Chen , Yang Wang

{"title":"Design, synthesis and biological evaluation of biaryl amide derivatives as modulators of multi-drug resistance","authors":"Ying-Yuan Peng , Zhi-Xian Shi , Min Yu , Sami Karam , Zhi-Long Chen , Yang Wang","doi":"10.1016/j.ejmech.2024.117090","DOIUrl":"10.1016/j.ejmech.2024.117090","url":null,"abstract":"<div><div>The emergence of multi-drug resistance (MDR) presents a significant impediment to the efficacy of cancer treatment. Aberrant expression of ABC (ATP-binding cassette) transporters is acknowledged as one of the underlying factors contributing to MDR. P-glycoprotein (P-gp, MDR1, ABCB1), breast cancer resistance protein (BCRP, ABCG2), and MDR-associated protein 1 (MRP1, ABCC1) are members of the ABC transporter, and their over-expression usually occurs in drug-resistant tumor cells. In this work, the structure-activity relationships of the biaryl amide skeleton were systematically investigated via structural optimization step by step, which led to the identification of an exceptionally potent resistance reversal agent, <strong>D2</strong>. Compound <strong>D2</strong> effectively reversed MDR to paclitaxel and cisplatin in A2780/T, A2780/CDDP and A549/T cell lines. It could directly bind to P-gp and downregulate the expression of both P-gp and MRP1. The treatment with <strong>D2</strong> increased the intracellular accumulation of Rh123 and inhibited P-gp-mediated drug efflux of Rh123 in A2780/T cells. Therefore, compound <strong>D2</strong> exhibits promising potential in overcoming multidrug resistance (MDR) induced by P-gp in cancer.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"282 ","pages":"Article 117090"},"PeriodicalIF":6.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684648","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

Antibacterial and antifungal pyrazoles based on different construction strategies 基于不同构建策略的抗菌和抗真菌吡唑

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-11-20 DOI: 10.1016/j.ejmech.2024.117081

Muneeb Ur Rehman , Fang He , Xi Shu, Ju Guo, Ziwei Liu, Shuang Cao, Sihui Long

{"title":"Antibacterial and antifungal pyrazoles based on different construction strategies","authors":"Muneeb Ur Rehman , Fang He , Xi Shu, Ju Guo, Ziwei Liu, Shuang Cao, Sihui Long","doi":"10.1016/j.ejmech.2024.117081","DOIUrl":"10.1016/j.ejmech.2024.117081","url":null,"abstract":"<div><div>The growing prevalence of microbial infections, and antimicrobial resistance (AMR) stemming from the overuse and misuse of antibiotics, call for novel therapeutic agents, particularly ones targeting resistant microbial strains. Scientists are striving to develop innovative agents to tackle the rising microbial infections and abate the risk of AMR. Pyrazole, a five-membered heterocyclic compound belonging to the azole family, is a versatile scaffold and serves as a core structure in many drugs with antimicrobial and other therapeutic effects. In this review, we have updated pyrazole-based antibacterial and antifungal agents mainly developed between 2016 and 2024, by combining with diverse pharmacophores such as coumarin, thiazole, oxadiazole, isoxazole, indole, etc. Meanwhile, the various strategies (molecular hybridization, bioisosterism, scaffold hopping, multicomponent reactions, and catalyst-free synthesis) for integrating different functional groups with the pyrazole ring are discussed. Additionally, structure-activity relationships of these pyrazole derivatives, i.e., how structural modifications impact their selectivity and therapeutic potential against bacterial and fungal strains, are highlighted. This review provides insights into designing next-generation antimicrobials to combat AMR, and offers valuable perspectives to the scientists working on heterocyclic compounds with diverse bioactivities.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"282 ","pages":"Article 117081"},"PeriodicalIF":6.0,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142679101","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 potent and selective factor XIa inhibitors incorporating triazole-based benzoic acid as novel P2’ fragments: Molecular dynamics simulations and anticoagulant activity 发现以三唑基苯甲酸为新型 P2'片段的强效和选择性因子 XIa 抑制剂：分子动力学模拟与抗凝活性

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-11-19 DOI: 10.1016/j.ejmech.2024.117067

Linjun Dai , Yanqing Qiu , Qingrui Xu , Feng Yang , Boquan Ren , Xinyu Zhuang , Ruixin Li , Junhao Xing , Yan-Jun Xu , Qing Li

{"title":"Discovery of potent and selective factor XIa inhibitors incorporating triazole-based benzoic acid as novel P2’ fragments: Molecular dynamics simulations and anticoagulant activity","authors":"Linjun Dai , Yanqing Qiu , Qingrui Xu , Feng Yang , Boquan Ren , Xinyu Zhuang , Ruixin Li , Junhao Xing , Yan-Jun Xu , Qing Li","doi":"10.1016/j.ejmech.2024.117067","DOIUrl":"10.1016/j.ejmech.2024.117067","url":null,"abstract":"<div><div>Factor XIa (FXIa) has emerged as a novel anticoagulant target with a reduced risk of bleeding. However, due to the nearly identical residues it shares with its closest homologue, plasma kallikrein (PKa), only a few selective FXIa inhibitors have been reported. Herein, we describe the discovery of novel triazole-based pyridone derivatives as potent and selective FXIa inhibitors. Structural optimization identified triazole-based benzoic acids as optimal P2′ fragments. The representative compound <strong>(S)-10h</strong> (IC<sub>50</sub> = 0.38 nM for FXIa) was approximately 3-fold more potent than asundexian for FXIa, along with up to 150-fold selectivity over PKa (13-fold for asundexian) and up to 100,000-fold selectivity over FXa and thrombin (5000-fold for asundexian). Extensive molecular dynamics simulations and free energy calculations revealed that electrostatic interactions with varied residues near the binding site, particularly the loop at the bottom of the S2’ pocket (IP-loop), are critical factors contributing to the improved selectivity over PKa. Calculations of electrostatic potential (ESP) surfaces illustrated that FXIa forms a more positive ESP than PKa, thrombin, and FXa, which attracts the carboxylic acid group of the designed compounds, enhancing both potency and selectivity. Moreover, compound <strong>(S)-10h</strong> demonstrated potent in vitro anticoagulant activity with an EC<sub>1.5X</sub> value of 0.55 μM for aPTT, without interfering with PT up to 100 μM. Thus, compound <strong>(S)-10h</strong> represents a promising lead for further optimization as a novel anticoagulant agent.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"282 ","pages":"Article 117067"},"PeriodicalIF":6.0,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142671025","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

Design, synthesis, and biological evaluation of novel highly potent FXR agonists bearing piperidine scaffold 带有哌啶支架的新型强效 FXR 激动剂的设计、合成和生物学评价

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-11-19 DOI: 10.1016/j.ejmech.2024.117082

Wenxin Wang , Zongyu Cai , Zhilin Liang , Zibin Liao , Yuxia Liu , Xinqian Geng , Yuanqian Yang , Yisi Chen , Zibin Huang , Ying Yang , Zheng Li

{"title":"Design, synthesis, and biological evaluation of novel highly potent FXR agonists bearing piperidine scaffold","authors":"Wenxin Wang , Zongyu Cai , Zhilin Liang , Zibin Liao , Yuxia Liu , Xinqian Geng , Yuanqian Yang , Yisi Chen , Zibin Huang , Ying Yang , Zheng Li","doi":"10.1016/j.ejmech.2024.117082","DOIUrl":"10.1016/j.ejmech.2024.117082","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatohepatitis (MASH) has become a serious threat to human health, which exhibited an increasing prevalence globally. Recently, the farnesoid X receptor (FXR) has been identified as a promising strategy for the treatment of MASH by regulating multiple pathogenesis. In this study, a new series of FXR agonists bearing piperidine scaffold was designed to reduce the high lipophilicity of the existing FXR agonists. After comprehensive multiparameter optimization, LZ-007 was discovered as a highly potent FXR agonist with suitable stability in liver microsomes of multiple species. LZ-007 exhibited highly oral bioavailability and targeted tissue exposure in the liver and ileum, while the plasma exposure is low, which might minimize the systemic side effects. Moreover, LZ-007 was significantly up-regulated the expressions of FXR and its downstream genes in the liver and ileum. In MASH model, LZ-007 exerted potent anti-MASH effects by regulating the multiple signal pathways related to lipid metabolism, oxidative stress, inflammation and fibrosis. In a 30-day toxicity study, no apparent adverse effects were observed in LZ-007 treated groups, even at the high doses of 250 and 500 mg/kg. With the positive pharmacodynamics and safety profiles, LZ-007 is worthy of further evaluation as a new anti-MASH agent.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"282 ","pages":"Article 117082"},"PeriodicalIF":6.0,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673791","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

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 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

{"title":"Design, synthesis and anti-tumor evaluation of novel pyrimidine and quinazoline analogues","authors":"Ren-Jie Lin, Lin Xie, Tian-Yu Gao, Yi-Zhou Yang, Lan Huang, Kui Cheng, Zhi-Peng Chen","doi":"10.1016/j.ejmech.2024.117057","DOIUrl":"10.1016/j.ejmech.2024.117057","url":null,"abstract":"<div><div>Disrupting microtubule dynamics has emerged as a promising strategy for cancer therapy. Novel trimethoxyanilino-substituted pyrimidine and quinazoline derivatives were designed and synthesized to serve as potent microtubule-inhibiting agents with anti-proliferative activity. Compound <strong>2k</strong> demonstrates high efficacy against B16–F10 cancer cells at low nanomolar concentrations, with an IC<sub>50</sub> of 0.098 ± 0.006 μM, which is comparable to colchicine. Mechanistic studies have revealed that <strong>2k</strong> has the ability to inhibit microtubule protein polymerization <em>in vitro</em>, resulting in cell cycle arrest and apoptosis. Furthermore, <strong>2k</strong> inhibits tumor cell migration and exhibits significant anti-tumor efficacy in a melanoma tumor model without causing obvious toxicity. In summary, the pyrimidine derivative <strong>2k</strong> exhibits excellent anticancer activity and provides a new scaffold for the development of novel microtubule inhibitors, which deserves further in-depth research.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"282 ","pages":"Article 117057"},"PeriodicalIF":6.0,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665249","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

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 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":"10.1016/j.ejmech.2024.117078","url":null,"abstract":"<div><div>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 <strong>D13</strong> showed notable inhibitory activity (IC<sub>50</sub> = 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 <strong>D13</strong> exhibited superior antiproliferative activity (IC<sub>50</sub> = 38 μM) by arresting G0/G1 cell cycle, facilitating cell apoptosis and suppressing the MAPK signaling pathway. In the <em>in vivo</em> study, <strong>D13</strong> displayed significant antitumor activity in a Huh7 xenograft model and possessed favorable druggability with acceptable oral bioavailability (<em>F</em> = 54 %) and half-life (<em>t</em><sub>1/2</sub> = 10.57 h). Collectively, this study lays a robust foundation for further optimization of the tail heterocycle skeleton in SHP2 allosteric inhibitors.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"282 ","pages":"Article 117078"},"PeriodicalIF":6.0,"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 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":"10.1016/j.ejmech.2024.117079","url":null,"abstract":"<div><div>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, <strong>NP18</strong>, which is developed from the covalent AR-NTD antagonist EPI-002, and effectively degrades both AR-FL and AR-V7 in 22Rv1 cells (DC<sub>50</sub>: 18 and 26 nM respectively). Mechanistically, <strong>NP18</strong> 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, <strong>NP18</strong> exhibited remarkably superior antitumor activity in both 22Rv1 xenograft and patient-derived xenograft (PDX) models than EPI-002. Taken together, these findings highlight <strong>NP18</strong> as a promising candidate to counteract AR splice variant-driven resistance.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"282 ","pages":"Article 117079"},"PeriodicalIF":6.0,"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 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 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":"10.1016/j.ejmech.2024.117062","url":null,"abstract":"<div><div>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 <strong>C6</strong>, obtained based on precise structural optimization of the linker, has been shown to effectively degrade PARP1 with a DC<sub>50</sub> value of 58.14 nM. Furthermore, <strong>C6</strong> 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 <strong>C6</strong> alongside Irinotecan for CRC patients harboring BRCA mutations in CRC.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"282 ","pages":"Article 117062"},"PeriodicalIF":6.0,"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 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

{"title":"Novel potent SOS1 inhibitors containing a tricyclic quinazoline scaffold: A joint view of experiments and simulations","authors":"Luolong Qing , Zhengzai Cheng , Juan Xu , Ziwei Wang , Yuanyuan Li , Mario Gauthier , Silong Zhang , Huan He","doi":"10.1016/j.ejmech.2024.117065","DOIUrl":"10.1016/j.ejmech.2024.117065","url":null,"abstract":"<div><div>Small molecules that possess the ability to regulate the interactions between Son of Sevenless 1 (SOS1) and Kristen rat sarcoma (KRAS) offer immense potential in the realm of cancer therapy. In this study, we present a novel series of SOS1 inhibitors featuring a tricyclic quinazoline scaffold. Notably, we have identified compound <strong>8d</strong>, which demonstrates the highest potency with an IC<sub>50</sub> value of 5.1 nM for disrupting the KRAS:SOS1 interaction. Compound <strong>8d</strong> exhibits a promising pharmacokinetic profile and achieves a remarkable 70.5 % inhibition of tumor growth in pancreas tumor xenograft models. Furthermore, molecular dynamic simulations have unveiled that the tricyclic quinazoline derivatives exhibit extensive interaction with Tyr884, a crucial residue for the recognition between SOS1 and KRAS. Our findings provide fresh insights into the design of future SOS1 inhibitors, paving the way for innovative therapeutic strategies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"282 ","pages":"Article 117065"},"PeriodicalIF":6.0,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665582","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