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 (S)-10h (IC50 = 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 (5,000-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 (S)-10h demonstrated potent in vitro anticoagulant activity with an EC1.5X value of 0.55 μM for aPTT, without interfering with PT up to 100 μM. Thus, compound (S)-10h represents a promising lead for further optimization as a novel anticoagulant agent.
{"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":"https://doi.org/10.1016/j.ejmech.2024.117067","url":null,"abstract":"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 (5,000-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.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"13 1","pages":""},"PeriodicalIF":6.7,"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}
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.
{"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":"https://doi.org/10.1016/j.ejmech.2024.117082","url":null,"abstract":"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.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"57 1","pages":""},"PeriodicalIF":6.7,"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}
Pub Date : 2024-11-18DOI: 10.1016/j.ejmech.2024.117057
Ren-Jie Lin, Lin Xie, Tian-Yu Gao, Yi-Zhou Yang, Lan Huang, Kui Cheng, Zhi-Peng Chen
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 2k demonstrates high efficacy against B16–F10 cancer cells at low nanomolar concentrations, with an IC50 of 0.098 ± 0.006 μM, which is comparable to colchicine. Mechanistic studies have revealed that 2k has the ability to inhibit microtubule protein polymerization in vitro, resulting in cell cycle arrest and apoptosis. Furthermore, 2k inhibits tumor cell migration and exhibits significant anti-tumor efficacy in a melanoma tumor model without causing obvious toxicity. In summary, the pyrimidine derivative 2k exhibits excellent anticancer activity and provides a new scaffold for the development of novel microtubule inhibitors, which deserves further in-depth research.
{"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":"https://doi.org/10.1016/j.ejmech.2024.117057","url":null,"abstract":"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.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"169 1","pages":""},"PeriodicalIF":6.7,"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}
Pub Date : 2024-11-18DOI: 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
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.
{"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 <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.","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}
Pub Date : 2024-11-18DOI: 10.1016/j.ejmech.2024.117079
Si Ha, Chenxuan Ji, Jiaqi Yang, Maoxu Xiao, Ziyi Xu, Wei-Wei Pan, Hua Xiang, Guoshun Luo
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.
{"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, <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.","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}
Pub Date : 2024-11-17DOI: 10.1016/j.ejmech.2024.117077
Suxing Jin, Chenyao Feng, Xiaoyong Wang
Platinum drugs are the most widely used chemotherapeutics to treat various tumors. Their primary mode of action is supposed to be inducing apoptosis of cancer cells via covalent binding to DNA. This mechanism has shackled the design of new platinum drugs for many years. Mounting evidence shows that many platinum complexes form non-covalent adducts with DNA or interact with proteins to exhibit significant antitumor activity, thus implying some distinct mechanisms from that of traditional platinum drugs. These unconventional examples indicate that covalent DNA binding is not the precondition for the antitumor activity of platinum complexes, and diversified reactions or interactions with biomolecules, organelles, signal pathways, or immune system could lead to the antitumor activity of platinum complexes. The atypical mechanisms break the classical DNA-only paradigm and structure−activity relationships, thus opening a wide avenue for the design of innovative platinum anticancer drugs.
铂类药物是治疗各种肿瘤最广泛使用的化疗药物。它们的主要作用方式是通过与 DNA 的共价结合诱导癌细胞凋亡。这种机制多年来一直束缚着新铂类药物的设计。越来越多的证据表明，许多铂复合物与 DNA 形成非共价加合物，或与蛋白质相互作用，从而表现出显著的抗肿瘤活性，这意味着与传统铂类药物的机制不同。这些非传统的例子表明，DNA共价结合并不是铂复合物抗肿瘤活性的前提条件，与生物大分子、细胞器、信号通路或免疫系统的多样化反应或相互作用可能导致铂复合物的抗肿瘤活性。非典型机制打破了经典的纯 DNA 范式和结构-活性关系，从而为设计创新的铂类抗癌药物开辟了一条广阔的道路。
{"title":"DNA or Not DNA —That is the Question Determining the Design of Platinum Anticancer Drugs","authors":"Suxing Jin, Chenyao Feng, Xiaoyong Wang","doi":"10.1016/j.ejmech.2024.117077","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117077","url":null,"abstract":"Platinum drugs are the most widely used chemotherapeutics to treat various tumors. Their primary mode of action is supposed to be inducing apoptosis of cancer cells via covalent binding to DNA. This mechanism has shackled the design of new platinum drugs for many years. Mounting evidence shows that many platinum complexes form non-covalent adducts with DNA or interact with proteins to exhibit significant antitumor activity, thus implying some distinct mechanisms from that of traditional platinum drugs. These unconventional examples indicate that covalent DNA binding is not the precondition for the antitumor activity of platinum complexes, and diversified reactions or interactions with biomolecules, organelles, signal pathways, or immune system could lead to the antitumor activity of platinum complexes. The atypical mechanisms break the classical DNA-only paradigm and structure−activity relationships, thus opening a wide avenue for the design of innovative platinum anticancer drugs.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"76 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665580","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}
Pub Date : 2024-11-17DOI: 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
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.
{"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 <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.","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}
Pub Date : 2024-11-17DOI: 10.1016/j.ejmech.2024.117065
Luolong Qing, Zhengzai Cheng, Juan Xu, Ziwei Wang, Yuanyuan Li, Mario Gauthier, Silong Zhang, Huan He
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 8d, which demonstrates the highest potency with an IC50 value of 5.1 nM for disrupting the KRAS:SOS1 interaction. Compound 8d 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.
{"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":"https://doi.org/10.1016/j.ejmech.2024.117065","url":null,"abstract":"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.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"171 1","pages":""},"PeriodicalIF":6.7,"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}
Pub Date : 2024-11-16DOI: 10.1016/j.ejmech.2024.117052
Deng-Gao Zhao, JieYing Liu, Zhengxi Su, Wenbo Zou, Qianwei Zhou, Ting Yin, Tan Jiyao, Yan-Yan Ma
Kinesin spindle protein (KSP) plays a crucial role during mitosis, making it an attractive target for cancer treatment. Herein, we report the design, synthesis, and evaluation of the first series of KSP degraders by using the utilization of the proteolysis-targeting chimera (PROTAC) technology. Compound 21 was identified as a potent KSP degrader with a DC50 (concentration causing 50% of protein degradation) value of 114.8 nM and a Dmax (maximum degradation) of 90% in the HCT-116 cells. Compound 21 showed strong antiproliferative activity against HCT-116 cells with an IC50 values of 10 nM. Mechanistic investigations revealed that 21 causes the cell arrest at the G2/M phase and subsequent cell apoptosis. In addition, 21 demonstrated more significant inhibition of tumor growth in an HCT-116 xenograft model compared to its parent compound 1. Our findings suggest that 21 may become the promising leads for further development.
{"title":"Discovery of novel KSP-targeting PROTACs with potent antitumor effects in Vitro and in Vivo","authors":"Deng-Gao Zhao, JieYing Liu, Zhengxi Su, Wenbo Zou, Qianwei Zhou, Ting Yin, Tan Jiyao, Yan-Yan Ma","doi":"10.1016/j.ejmech.2024.117052","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117052","url":null,"abstract":"Kinesin spindle protein (KSP) plays a crucial role during mitosis, making it an attractive target for cancer treatment. Herein, we report the design, synthesis, and evaluation of the first series of KSP degraders by using the utilization of the proteolysis-targeting chimera (PROTAC) technology. Compound <strong>21</strong> was identified as a potent KSP degrader with a DC<sub>50</sub> (concentration causing 50% of protein degradation) value of 114.8 nM and a D<sub>max</sub> (maximum degradation) of 90% in the HCT-116 cells. Compound <strong>21</strong> showed strong antiproliferative activity against HCT-116 cells with an IC<sub>50</sub> values of 10 nM. Mechanistic investigations revealed that <strong>21</strong> causes the cell arrest at the G2/M phase and subsequent cell apoptosis. In addition, <strong>21</strong> demonstrated more significant inhibition of tumor growth in an HCT-116 xenograft model compared to its parent compound <strong>1.</strong> Our findings suggest that <strong>21</strong> may become the promising leads for further development.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"12 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142642895","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}
Pub Date : 2024-11-16DOI: 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
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.
肌萎缩性脊髓侧索硬化症（ALS）是一种以运动神经元变性、肌肉无力和最终瘫痪为特征的进行性神经退行性疾病，本文探讨了纳米技术在肌萎缩性脊髓侧索硬化症（ALS）的治疗和诊断中的变革潜力。纳米技术可在多个领域提供创新解决方案，包括靶向给药、神经保护、基因治疗和编辑、生物标记检测、先进成像技术和组织工程。通过提高治疗干预的精确性和有效性，纳米技术促进了一些关键的进步，如穿越血脑屏障、靶向特定细胞类型、实现持续治疗释放，以及针对 ALS 复杂的病理生理学实现组合疗法。尽管前景广阔，但这些方法的临床转化仍面临挑战，包括潜在的细胞毒性、生物相容性和监管合规性，这些都必须通过严格的研究和测试来解决。这篇综述强调了纳米技术在 ALS 靶向给药和基因治疗/编辑中的应用，并借鉴了作者之前在各种纳米技术平台上的研究成果，说明了克服药物和基因给药中类似障碍的策略。通过缩小前沿技术与临床应用之间的差距，本文旨在强调纳米技术在塑造 ALS 治疗未来方面的重要作用。
{"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}
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