Pub Date : 2025-01-20DOI: 10.1016/j.ejmech.2025.117305
Tao Li, Xianqiang Yu, Xinyao Wan, Jing Liu, Jie Zheng, Ziyu Sun, Yi Zhao, Jiakang Chen, Hongli Chen, Yifeng Yang, Biao Jiang
Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with poor prognosis. Antibody-drug conjugates (ADCs) and their combinations with various anti-tumor drugs have made great progress. Camptothecin, and its derivatives (Dxd, SN-38 or exatecan) targeted TOP1 are effective payloads due to their potent anti-tumor activity. ADCs offer a promising avenue, particularly when integrated with synthetic lethality strategies. In this study, the ADC SA-7-49 is engineered by conjugating exatecan to an anti-TROP2 antibody. The synthetic lethality between camptothecin and the ataxia telangiectasia–mutated and rad3-related (ATR) inhibitors in PDAC cells has been identified through a comprehensive screening of DNA damage response pathways. Drug interactions are quantified using Zero interaction potency (ZIP) scores. RNA sequencing is employed to elucidate the mechanisms driving synergistic effects. ATR inhibitors synergize with camptothecin by inducing apoptosis via ATR-Chk1 pathway inhibition. Knockdown of ATR enhances the sensitivity of PDAC cells to camptothecin and SA-7-49. SA-7-49 selectively targets and eradicates PDAC cells and xenografts without side effects, augmenting anti-tumor activity via synthetic lethality. Our findings reveal a novel therapeutic strategy by integrating ADC technology with synthetic lethality in PDAC cells.
{"title":"Exploiting Synthetic Lethality in PDAC with Antibody Drug Conjugates and ATR inhibition","authors":"Tao Li, Xianqiang Yu, Xinyao Wan, Jing Liu, Jie Zheng, Ziyu Sun, Yi Zhao, Jiakang Chen, Hongli Chen, Yifeng Yang, Biao Jiang","doi":"10.1016/j.ejmech.2025.117305","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117305","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with poor prognosis. Antibody-drug conjugates (ADCs) and their combinations with various anti-tumor drugs have made great progress. Camptothecin, and its derivatives (Dxd, SN-38 or exatecan) targeted TOP1 are effective payloads due to their potent anti-tumor activity. ADCs offer a promising avenue, particularly when integrated with synthetic lethality strategies. In this study, the ADC <strong>SA-7-49</strong> is engineered by conjugating exatecan to an anti-TROP2 antibody. The synthetic lethality between camptothecin and the ataxia telangiectasia–mutated and rad3-related (ATR) inhibitors in PDAC cells has been identified through a comprehensive screening of DNA damage response pathways. Drug interactions are quantified using Zero interaction potency (ZIP) scores. RNA sequencing is employed to elucidate the mechanisms driving synergistic effects. ATR inhibitors synergize with camptothecin by inducing apoptosis via ATR-Chk1 pathway inhibition. Knockdown of ATR enhances the sensitivity of PDAC cells to camptothecin and <strong>SA-7-49</strong>. <strong>SA-7-49</strong> selectively targets and eradicates PDAC cells and xenografts without side effects, augmenting anti-tumor activity via synthetic lethality. Our findings reveal a novel therapeutic strategy by integrating ADC technology with synthetic lethality in PDAC cells.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"27 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991072","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}
Immunotherapy has become one of the most revolutionary modalities for cancer treatment with the approval of many anti-PD-L1 (programmed cell death-ligand 1) /PD-1 (programmed cell death-1) monoclonal antibodies (mAbs). However, anti-PD-L1/PD-1 mAbs suffer from several drawbacks including limited clinical efficacy (∼20%), poor pharmacokinetics, and the development of immune resistance. Hence, the search for PD-1/PD-L1-based combination therapies and other PD-L1-based bifunctional small molecule modulators [e.g. PD-L1/HDAC (Histone Deacetylase), PD-L1/CXCL12 (C-X-C chemokine ligand 12), PD-L1/Tubulin, PD-L1/IDO1 (Indoleamine 2,3 dioxygenase 1), PD-L1/PARP (Poly(ADP-ribose) polymerase), PD-L1/STING (Stimulator of interferon genes), and PD-L1/NAMPT (Nicotinamide phosphoribosyltransferase)-targeting dual inhibitors] has been intensified with considerable strides achieved in the past couple of years. Herein, we summarize the latest development of bifunctional small molecules as immunotherapy for tumor treatment, including those PD-L1-based, A2AR (Adenosine 2A receptor)-based, IDO1-based, Toll-like receptor (TLR)-based, SHP2 (Src homology 2 domain-containing phosphatase 2)-based, and HPK1 (Hematopoietic progenitor kinase 1)-based dual-acting compounds. In addition, we also summarize the tumorigenesis and synergy mechanism of various targets. Finally, the challenges and future directions for bifunctional small molecules for cancer immunotherapy are also discussed in detail.
{"title":"Research Progress in Bifunctional small molecules for cancer immunotherapy","authors":"Binbin Cheng, Hongqiao Li, Yimeng Hong, Yingxing Zhou, Jianjun Chen, Chuxiao Shao, Zhihua Kong","doi":"10.1016/j.ejmech.2025.117289","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117289","url":null,"abstract":"Immunotherapy has become one of the most revolutionary modalities for cancer treatment with the approval of many anti-PD-L1 (programmed cell death-ligand 1) /PD-1 (programmed cell death-1) monoclonal antibodies (mAbs). However, anti-PD-L1/PD-1 mAbs suffer from several drawbacks including limited clinical efficacy (∼20%), poor pharmacokinetics, and the development of immune resistance. Hence, the search for PD-1/PD-L1-based combination therapies and other PD-L1-based bifunctional small molecule modulators [e.g. PD-L1/HDAC (Histone Deacetylase), PD-L1/CXCL12 (C-X-C chemokine ligand 12), PD-L1/Tubulin, PD-L1/IDO1 (Indoleamine 2,3 dioxygenase 1), PD-L1/PARP (Poly(ADP-ribose) polymerase), PD-L1/STING (Stimulator of interferon genes), and PD-L1/NAMPT (Nicotinamide phosphoribosyltransferase)-targeting dual inhibitors] has been intensified with considerable strides achieved in the past couple of years. Herein, we summarize the latest development of bifunctional small molecules as immunotherapy for tumor treatment, including those PD-L1-based, A<sub>2A</sub>R (Adenosine 2A receptor)-based, IDO1-based, Toll-like receptor (TLR)-based, SHP2 (Src homology 2 domain-containing phosphatase 2)-based, and HPK1 (Hematopoietic progenitor kinase 1)-based dual-acting compounds. In addition, we also summarize the tumorigenesis and synergy mechanism of various targets. Finally, the challenges and future directions for bifunctional small molecules for cancer immunotherapy are also discussed in detail.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"26 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989538","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 : 2025-01-19DOI: 10.1016/j.ejmech.2025.117293
Yanping Zeng, Jian Xiao, Li Shi, Yangsha Li, Yuanxin Xu, Jiayun Zhou, Xiao Dong, Haiyang Hou, Chao Zhong, Gang Cheng, Yi Chen, Naixia Zhang, Yanfen Fang, Youhong Hu
Targeted protein degradation through autophagosome-tethering compounds (ATTECs) that bypasses the ubiquitination process has garnered increasing attention. LC3B, a key protein in autophagosome formation, recruits substrates into the autophagy-lysosome system for degradation. In this study, we systematically optimized 2,4-quinazolinedione derivatives as LC3B-recruiting fragments, utilizing the CDK9 indicator. By attaching the designed LC3B-recruiting fragment to CDK9 inhibitor SNS-032 through a linker, the resulting bifunctional ATTEC molecule simultaneously degraded CDK9 and its associated Cyclin T1. Two-dimensional NMR experiments confirmed the direct interaction between the novel LC3B-recruiting fragments and LC3B. Mechanistic studies elucidated that degradation occurred via an LC3B-dependent autophagy-lysosomal pathway. Additionally, the general applicability of leveraging LC3B-recruiting fragments linked to inhibitors for the targeted degradation of protein complexes was validated with PRC2 and CDK2/4/6 along with their respective Cyclins. This work provides a series of novel LC3B-recruiting fragments that enrich the ATTEC toolbox and can be applied to the degradation of diverse intracellular disease-causing proteins.
{"title":"Discovery of 2,4-Quinazolinedione Derivatives as LC3B Recruiters in the Facilitation of Protein Complex Degradations","authors":"Yanping Zeng, Jian Xiao, Li Shi, Yangsha Li, Yuanxin Xu, Jiayun Zhou, Xiao Dong, Haiyang Hou, Chao Zhong, Gang Cheng, Yi Chen, Naixia Zhang, Yanfen Fang, Youhong Hu","doi":"10.1016/j.ejmech.2025.117293","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117293","url":null,"abstract":"Targeted protein degradation through autophagosome-tethering compounds (ATTECs) that bypasses the ubiquitination process has garnered increasing attention. LC3B, a key protein in autophagosome formation, recruits substrates into the autophagy-lysosome system for degradation. In this study, we systematically optimized 2,4-quinazolinedione derivatives as LC3B-recruiting fragments, utilizing the CDK9 indicator. By attaching the designed LC3B-recruiting fragment to CDK9 inhibitor SNS-032 through a linker, the resulting bifunctional ATTEC molecule simultaneously degraded CDK9 and its associated Cyclin T1. Two-dimensional NMR experiments confirmed the direct interaction between the novel LC3B-recruiting fragments and LC3B. Mechanistic studies elucidated that degradation occurred <em>via</em> an LC3B-dependent autophagy-lysosomal pathway. Additionally, the general applicability of leveraging LC3B-recruiting fragments linked to inhibitors for the targeted degradation of protein complexes was validated with PRC2 and CDK2/4/6 along with their respective Cyclins. This work provides a series of novel LC3B-recruiting fragments that enrich the ATTEC toolbox and can be applied to the degradation of diverse intracellular disease-causing proteins.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"22 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989537","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 : 2025-01-19DOI: 10.1016/j.ejmech.2025.117291
Hang Zhang, Zhihao Xu, Zhengyu Xu, Shaopan Bian, Ning Qiao, Xiaodi Wang, Mingwei Zhang, Mengzhen Zhang, Xuanlong Zhen, Di Wu, Haiwei Xu
Gastric cancer remains one of the global health threats for human beings. However, the therapeutic efficacy of the widely-used chemotherapy is usually limited due to the lack of specificity and the related toxicity. Only limited therapeutic agents were demonstrated to show selective and potent inhibitory activity to gastric cancer cells. In this study, we report the first α, β-unsaturated lactam-based andrographolide derivative P16 with the ability to potently and selectively inhibit the proliferation and migration of gastric cancer cells MGC-803. Moreover, the in vivo studies showed that P16 exhibited remarking anti-gastric cancer activity by significantly reducing the growth of tumor without losing the body weight. Further anticancer mechanistic studies indicated that P16 exerted its potent and selective anti-gastric cancer effect by arresting cell cycle at G2/M phase and inducing cancer cell apoptosis through intrinsic mitochondria-mediated pathway. Notably, for the first time, we found that andrographolide derivative P16 could reduce the activities of the ERK/c-Fos/Jun pathway to exert the anti-gastric cancer efficiency. This is the first time to reveal the novel role of ERK/c-Fos/Jun signaling in andrographolide derivative-mediated anti-gastric cancer processes. Overall. derivative P16 represents a valuable candidate for new therapeutic agent discovery in gastric cancer chemotherapy. In addition, pharmacological characterizations of derivative P16, together with another 33 new semi-synthesized andrographolide derivatives, provides a systematic structure-activity relationship (SAR) analysis for this class of compounds, elucidating useful information on structural requirements for potent and selective anti-gastric cancer inhibition.
{"title":"The development of α, β-unsaturated lactam-based andrographolide derivatives as anti-gastric cancer agents with the ability of inhibiting the ERK/c-Fos/Jun pathway","authors":"Hang Zhang, Zhihao Xu, Zhengyu Xu, Shaopan Bian, Ning Qiao, Xiaodi Wang, Mingwei Zhang, Mengzhen Zhang, Xuanlong Zhen, Di Wu, Haiwei Xu","doi":"10.1016/j.ejmech.2025.117291","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117291","url":null,"abstract":"Gastric cancer remains one of the global health threats for human beings. However, the therapeutic efficacy of the widely-used chemotherapy is usually limited due to the lack of specificity and the related toxicity. Only limited therapeutic agents were demonstrated to show selective and potent inhibitory activity to gastric cancer cells. In this study, we report the first α, β-unsaturated lactam-based andrographolide derivative <strong>P16</strong> with the ability to potently and selectively inhibit the proliferation and migration of gastric cancer cells MGC-803. Moreover, the <em>in vivo</em> studies showed that <strong>P16</strong> exhibited remarking anti-gastric cancer activity by significantly reducing the growth of tumor without losing the body weight. Further anticancer mechanistic studies indicated that <strong>P16</strong> exerted its potent and selective anti-gastric cancer effect by arresting cell cycle at <em>G2/M</em> phase and inducing cancer cell apoptosis through intrinsic mitochondria-mediated pathway. Notably, for the first time, we found that andrographolide derivative <strong>P16</strong> could reduce the activities of the ERK/c-Fos/Jun pathway to exert the anti-gastric cancer efficiency. This is the first time to reveal the novel role of ERK/c-Fos/Jun signaling in andrographolide derivative-mediated anti-gastric cancer processes. Overall. derivative <strong>P16</strong> represents a valuable candidate for new therapeutic agent discovery in gastric cancer chemotherapy. In addition, pharmacological characterizations of derivative <strong>P16,</strong> together with another 33 new semi-synthesized andrographolide derivatives, provides a systematic structure-activity relationship (SAR) analysis for this class of compounds, elucidating useful information on structural requirements for potent and selective anti-gastric cancer inhibition.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"13 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989539","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}
Artesunate, a semisynthetic derivative of artemisinin, is not only recommended as the first-line drug for treating severe malaria but also constitutes a significant member of Artemisinin-based Combination Therapy (ACTs), used in combination with other artemisinin derivatives for treating uncomplicated malaria. Beyond its potent antimalarial activity, artesunate has garnered considerable attention for its pharmacological effects, which encompass broad-spectrum anti-tumor, antiviral, and anti-inflammatory properties. It has collectively demonstrated superior drug tolerance, low toxicity, and mild side effects in cell line experiments in vitro, experimental animal models, and clinical drug studies, whether administered as a monotherapy or in combination with other agents. Examining its pharmacological action against different diseases will promote the exploration of novel drug applications for artesunate and increase its more comprehensive clinical application.
{"title":"Artesunate—multiple pharmacological effects beyond treating malaria","authors":"Yuzhi Chang, Tong Lyu, Xingyue Luan, Yiming Yang, Yaming Cao, Yue Qiu, Hui Feng","doi":"10.1016/j.ejmech.2025.117292","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117292","url":null,"abstract":"Artesunate, a semisynthetic derivative of artemisinin, is not only recommended as the first-line drug for treating severe malaria but also constitutes a significant member of Artemisinin-based Combination Therapy (ACTs), used in combination with other artemisinin derivatives for treating uncomplicated malaria. Beyond its potent antimalarial activity, artesunate has garnered considerable attention for its pharmacological effects, which encompass broad-spectrum anti-tumor, antiviral, and anti-inflammatory properties. It has collectively demonstrated superior drug tolerance, low toxicity, and mild side effects in cell line experiments in vitro, experimental animal models, and clinical drug studies, whether administered as a monotherapy or in combination with other agents. Examining its pharmacological action against different diseases will promote the exploration of novel drug applications for artesunate and increase its more comprehensive clinical application.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"12 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989540","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 : 2025-01-17DOI: 10.1016/j.ejmech.2025.117277
Uzma Azam, Muhammad Moazzam Naseer, Christophe Rochais
Alzheimer's disease (AD) remains a significant healthcare challenge, necessitating innovative therapeutic approaches to address its complex and multifactorial nature. Traditional drug discovery strategies targeting single molecular targets are not sufficient for the effective treatment of AD. In recent years, MTDLs have emerged as promising candidates for AD therapy, aiming to simultaneously modulate multiple pathological targets. Among the various strategies employed in MTDL design, pharmacophore hybridization offers a versatile approach to integrate diverse pharmacophoric features within a single molecular scaffold. This strategy provides access to a wide array of chemical space for the design and development of novel therapeutic agents. This review, therefore, provides a comprehensive overview of skeletal diversity exhibited by MTDLs designed recently for AD therapy based on pharmacophore hybridization approach. A diverse range of pharmacophoric elements and core scaffolds hybridized to construct MTDLs that has the potential to target multiple pathological features of AD including amyloid-beta aggregation, tau protein hyperphosphorylation, cholinergic dysfunction, oxidative stress, and neuroinflammation are discussed. Through the comprehensive analysis and integration of structural insights of key biomolecular targets, this review aims to enhance optimization efforts in MTDL design, ultimately striving towards a comprehensive cure for the multifaceted pathophysiology of the disease.
{"title":"Analysis of skeletal diversity of multi-target directed ligands (MTDLs) targeting Alzheimer’s disease","authors":"Uzma Azam, Muhammad Moazzam Naseer, Christophe Rochais","doi":"10.1016/j.ejmech.2025.117277","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117277","url":null,"abstract":"Alzheimer's disease (AD) remains a significant healthcare challenge, necessitating innovative therapeutic approaches to address its complex and multifactorial nature. Traditional drug discovery strategies targeting single molecular targets are not sufficient for the effective treatment of AD. In recent years, MTDLs have emerged as promising candidates for AD therapy, aiming to simultaneously modulate multiple pathological targets. Among the various strategies employed in MTDL design, pharmacophore hybridization offers a versatile approach to integrate diverse pharmacophoric features within a single molecular scaffold. This strategy provides access to a wide array of chemical space for the design and development of novel therapeutic agents. This review, therefore, provides a comprehensive overview of skeletal diversity exhibited by MTDLs designed recently for AD therapy based on pharmacophore hybridization approach. A diverse range of pharmacophoric elements and core scaffolds hybridized to construct MTDLs that has the potential to target multiple pathological features of AD including amyloid-beta aggregation, tau protein hyperphosphorylation, cholinergic dysfunction, oxidative stress, and neuroinflammation are discussed. Through the comprehensive analysis and integration of structural insights of key biomolecular targets, this review aims to enhance optimization efforts in MTDL design, ultimately striving towards a comprehensive cure for the multifaceted pathophysiology of the disease.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"8 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989545","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}
Incorporating fluorine-containing groups into the chemical skeleton is expected to enhance bioactivity and bioavailability. Directly introducing fluorine groups into the parthenolide skeleton remains challenging and limited. In this research, a series of novel fluorine-containing parthenolide derivatives were synthesized through late-stage diversification strategy. And the most promising derivate 1 exhibited good antiproliferative activity against NCI-H820 (IC50: 2.66 μM), Huh-7 (IC50: 2.36 μM), and PANC-1(IC50: 2.16 μM). The preliminary mechanism study indicated compound 1 strongly inhibited the colony formation number of NCI-H820, Huh-7 and PANC-1 cells and inhibited lung cancer metastasis with a dose-dependent manner through inhibiting STAT3 signaling pathway. Compound 16, a prodrug of compound 1, showed a significant improvement in aqueous solubility and oral bioavailability compared with parthenolide. Moreover, compound 16 significantly suppressed tumor growth in lung patient-derived tumor xenograft model without obvious toxicity. Based on the above results, we propose that compound 16 may be a promising lead compound for treatment of lung cancer.
{"title":"Discovery of Novel Fluorine-Containing Parthenolide Analogues as Potential Antitumor Agents","authors":"Xiyan Duan, Junqi Wang, Xiaoguang Huo, Zhuo Shen, Yahui Ding","doi":"10.1016/j.ejmech.2025.117283","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117283","url":null,"abstract":"Incorporating fluorine-containing groups into the chemical skeleton is expected to enhance bioactivity and bioavailability. Directly introducing fluorine groups into the parthenolide skeleton remains challenging and limited. In this research, a series of novel fluorine-containing parthenolide derivatives were synthesized through late-stage diversification strategy. And the most promising derivate 1 exhibited good antiproliferative activity against NCI-H820 (IC<sub>50</sub>: 2.66 μM), Huh-7 (IC<sub>50</sub>: 2.36 μM), and PANC-1(IC<sub>50</sub>: 2.16 μM). The preliminary mechanism study indicated compound 1 strongly inhibited the colony formation number of NCI-H820, Huh-7 and PANC-1 cells and inhibited lung cancer metastasis with a dose-dependent manner through inhibiting STAT3 signaling pathway. Compound 16, a prodrug of compound 1, showed a significant improvement in aqueous solubility and oral bioavailability compared with parthenolide. Moreover, compound 16 significantly suppressed tumor growth in lung patient-derived tumor xenograft model without obvious toxicity. Based on the above results, we propose that compound 16 may be a promising lead compound for treatment of lung cancer.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"4 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989546","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 : 2025-01-17DOI: 10.1016/j.ejmech.2025.117279
Kun Wang, Changgui Shi, Lu Liu, Hao Yan, Dalong Wang, Meiqing Ding, Jiaying Tong, Yeying He, Yina Hu, Chaoyue Chen, Di Cao, Fangjun Zhang, Xiaohui Zheng, Zhiguo Liu
Telomere repeat-binding factor 2 (TRF2) is a crucial component of the shelterin complex, commonly overexpressed in osteosarcoma (OS) and positively correlated with its progression. To date, effective TRF2 inhibitors for in vivo applications remain limited. In this study, a series of Flavokavain B derivatives were designed and synthesized, and their TRF2 inhibition and antitumor activity were evaluated. Among the tested compounds, the active compound F2 showed remarkable inhibition of TRF2 expression, along with potent antiproliferative activity in U2OS and MG63 cells, with IC50 values of 5.28 μM and 1.52 μM, respectively. Moreover, F2 significantly suppressed OS cell proliferation and induced apoptosis by accelerating telomere shortening and loss due to TRF2 inhibition. Mechanically, F2 selectively inhibited TRF2 protein expression and telomeric localization by directly binding to the TRF2TRFH domain. Furthermore, F2 demonstrated strong antitumor efficacy with minimal toxicity in an MG63-derived xenograft mouse model. These findings demonstrate that F2 is a promising drug candidate for the treatment of osteosarcoma.
{"title":"Design, synthesis, and biological evaluation of Flavokavain B derivatives as potent TRF2 inhibitors for the treatment of Osteosarcoma","authors":"Kun Wang, Changgui Shi, Lu Liu, Hao Yan, Dalong Wang, Meiqing Ding, Jiaying Tong, Yeying He, Yina Hu, Chaoyue Chen, Di Cao, Fangjun Zhang, Xiaohui Zheng, Zhiguo Liu","doi":"10.1016/j.ejmech.2025.117279","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117279","url":null,"abstract":"Telomere repeat-binding factor 2 (TRF2) is a crucial component of the shelterin complex, commonly overexpressed in osteosarcoma (OS) and positively correlated with its progression. To date, effective TRF2 inhibitors for <em>in vivo</em> applications remain limited. In this study, a series of Flavokavain B derivatives were designed and synthesized, and their TRF2 inhibition and antitumor activity were evaluated. Among the tested compounds, the active compound <strong>F2</strong> showed remarkable inhibition of TRF2 expression, along with potent antiproliferative activity in U2OS and MG63 cells, with IC<sub>50</sub> values of 5.28 μM and 1.52 μM, respectively. Moreover, <strong>F2</strong> significantly suppressed OS cell proliferation and induced apoptosis by accelerating telomere shortening and loss due to TRF2 inhibition. Mechanically, <strong>F2</strong> selectively inhibited TRF2 protein expression and telomeric localization by directly binding to the TRF2<sub>TRFH</sub> domain. Furthermore, <strong>F2</strong> demonstrated strong antitumor efficacy with minimal toxicity in an MG63-derived xenograft mouse model. These findings demonstrate that <strong>F2</strong> is a promising drug candidate for the treatment of osteosarcoma.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"98 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988011","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 : 2025-01-17DOI: 10.1016/j.ejmech.2025.117286
Zi-Jie Song, Xiao-Fei Wu, Zhi-Ya Zhou, Jing-Jing Zhang, P.A.N. Yan-Yan, Xue Dong, Xuan Pang, Ya-Ping Xie, Juan Sun, Yu Zhang, Jie Qin
A library comprising twenty-four isosteric derivatives of celecoxib substituted with carboxylic acid (labeled as 5a-5x), was synthesized and characterized through 1H NMR, 13C NMR, HRMS, and elemental analysis. Molecular docking studies revealed that all compounds successfully docked into the binding pocket of COX-2, and the introduction of carboxyl group enhances the interaction between the derivatives and COX-2. The compounds were further evaluated for cell toxicity, and in vitro anti-inflammatory activity. Notably, compound 5l exhibited significant inhibition of both COX-2 and NO release in vitro in comparison to the standard compound, displaying the highest selectivity towards the COX-2 enzyme (SI = 295.9) in comparison to celecoxib (SI = 261.3). 5l also exhibited the most potent anti-inflammatory activity and safety (ulcer index = 5.2) in vivo comparable to celecoxib at the same concentration. Through the molecular modeling and dynamics analysis, it was observed that compound 5l effectively stabilized within the active binding site of COX-2 through strong hydrogen bond interactions, and through the ADMET studies investigated the physiochemical properties and drug-likeliness behavior of compound 5l. In conclusion, compound 5l demonstrated to be a potential selective COX-2 anti-inflammatory candidate with reduced gastrointestinal risks.
{"title":"Design, synthesis, and evaluation of carboxylic acid-substituted celecoxib isosteres as potential anti-inflammatory agents","authors":"Zi-Jie Song, Xiao-Fei Wu, Zhi-Ya Zhou, Jing-Jing Zhang, P.A.N. Yan-Yan, Xue Dong, Xuan Pang, Ya-Ping Xie, Juan Sun, Yu Zhang, Jie Qin","doi":"10.1016/j.ejmech.2025.117286","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117286","url":null,"abstract":"A library comprising twenty-four isosteric derivatives of celecoxib substituted with carboxylic acid (labeled as <strong>5a</strong>-<strong>5x</strong>), was synthesized and characterized through <sup>1</sup>H NMR, <sup>13</sup>C NMR, HRMS, and elemental analysis. Molecular docking studies revealed that all compounds successfully docked into the binding pocket of COX-2, and the introduction of carboxyl group enhances the interaction between the derivatives and COX-2. The compounds were further evaluated for cell toxicity, and <em>in vitro</em> anti-inflammatory activity. Notably, compound <strong>5l</strong> exhibited significant inhibition of both COX-2 and NO release <em>in vitro</em> in comparison to the standard compound, displaying the highest selectivity towards the COX-2 enzyme (SI = 295.9) in comparison to celecoxib (SI = 261.3). <strong>5l</strong> also exhibited the most potent anti-inflammatory activity and safety (ulcer index = 5.2) <em>in vivo</em> comparable to celecoxib at the same concentration. Through the molecular modeling and dynamics analysis, it was observed that compound <strong>5l</strong> effectively stabilized within the active binding site of COX-2 through strong hydrogen bond interactions, and through the ADMET studies investigated the physiochemical properties and drug-likeliness behavior of compound <strong>5l</strong>. In conclusion, compound <strong>5l</strong> demonstrated to be a potential selective COX-2 anti-inflammatory candidate with reduced gastrointestinal risks.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"83 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989544","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 : 2025-01-17DOI: 10.1016/j.ejmech.2025.117281
Heming Chen, Wei Su, Tingting Li, Yun Wang, Zhuangyu Li, Liyan Xiong, Zhe-Sheng Chen, Chuan Zhang, Tingfang Wang
Hepatic fibrosis, a widespread pathological process observed across various liver diseases, is acknowledged as a potentially reversible condition. In recent years, liver fibrosis has garnered extensive research attention, with a primary emphasis on developing drugs that can directly block or reverse this condition. This paper presents a comprehensive review of the design strategies for various anti-hepatic fibrosis agents that have been many efficacious small-molecule drugs. This review encompasses the synthesis and design of nuclear receptor ligands (such as VDR and Nurr7), kinase inhibitors (including ALK5 and JAK1), selective PDE inhibitors, small-molecule monomers derived from natural products, and other small molecules. The aim of this review is to provide promising avenues and valuable insights for the continued development of anti-hepatic fibrosis drugs.
{"title":"Recent advances in small molecule design strategies against hepatic fibrosis","authors":"Heming Chen, Wei Su, Tingting Li, Yun Wang, Zhuangyu Li, Liyan Xiong, Zhe-Sheng Chen, Chuan Zhang, Tingfang Wang","doi":"10.1016/j.ejmech.2025.117281","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117281","url":null,"abstract":"Hepatic fibrosis, a widespread pathological process observed across various liver diseases, is acknowledged as a potentially reversible condition. In recent years, liver fibrosis has garnered extensive research attention, with a primary emphasis on developing drugs that can directly block or reverse this condition. This paper presents a comprehensive review of the design strategies for various anti-hepatic fibrosis agents that have been many efficacious small-molecule drugs. This review encompasses the synthesis and design of nuclear receptor ligands (such as VDR and Nurr7), kinase inhibitors (including ALK5 and JAK1), selective PDE inhibitors, small-molecule monomers derived from natural products, and other small molecules. The aim of this review is to provide promising avenues and valuable insights for the continued development of anti-hepatic fibrosis drugs.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"9 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989547","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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