Pub Date : 2025-02-12DOI: 10.1016/j.ejmech.2025.117388
Siyu Xiu , Zhenyu Jia , Zhiqi Wang , Huiyu Liu , Cheng Shi , Xiaojiao Sun , Xiangyu Zhang , Xiaowei Chi , Zhenming Liu , Liangren Zhang
Lung squamous cell carcinoma (LUSC), a highly aggressive subtype of lung cancer, presents significant therapeutic challenges due to its complex molecular underpinnings. Recently, NSD3 has been identified as a key driver in the pathogenesis of LUSC, providing a new direction for targeted interventions. Herein, we report the rational design, synthesis, and comprehensive biological evaluation of a series of NSD3 inhibitors, culminating in the identification of compound A8, which demonstrates potent inhibitory activity against NSD3 and LUSC cell proliferation, with an IC50 of 0.355 μM in NCI–H1703 cells, and less toxicity to non-cancerous HEK293T cells. Cellular thermal shift assays confirmed the binding affinity of compound A8 for NSD3, promoting protein stabilization. Mechanistic investigations revealed that compound A8 induces apoptosis in LUSC cells in a dose-dependent manner and exhibits significant antitumor effects in both in vitro and in vivo models. Notably, compound A8 displayed favorable pharmacokinetic properties and efficaciously suppressed tumor growth in an NCI–H520 xenograft mouse model without observable adverse effects. These findings collectively establish compound A8 as a promising candidate for the development of targeted therapies against LUSC, highlighting the therapeutic potential of NSD3 inhibition.
{"title":"Design, synthesis, and antitumor activity of NSDs inhibitors targeting lung squamous cell carcinoma","authors":"Siyu Xiu , Zhenyu Jia , Zhiqi Wang , Huiyu Liu , Cheng Shi , Xiaojiao Sun , Xiangyu Zhang , Xiaowei Chi , Zhenming Liu , Liangren Zhang","doi":"10.1016/j.ejmech.2025.117388","DOIUrl":"10.1016/j.ejmech.2025.117388","url":null,"abstract":"<div><div>Lung squamous cell carcinoma (LUSC), a highly aggressive subtype of lung cancer, presents significant therapeutic challenges due to its complex molecular underpinnings. Recently, NSD3 has been identified as a key driver in the pathogenesis of LUSC, providing a new direction for targeted interventions. Herein, we report the rational design, synthesis, and comprehensive biological evaluation of a series of NSD3 inhibitors, culminating in the identification of compound <strong>A8</strong>, which demonstrates potent inhibitory activity against NSD3 and LUSC cell proliferation, with an IC<sub>50</sub> of 0.355 μM in NCI–H1703 cells, and less toxicity to non-cancerous HEK293T cells. Cellular thermal shift assays confirmed the binding affinity of compound <strong>A8</strong> for NSD3, promoting protein stabilization. Mechanistic investigations revealed that compound <strong>A8</strong> induces apoptosis in LUSC cells in a dose-dependent manner and exhibits significant antitumor effects in both <em>in vitro</em> and <em>in vivo</em> models. Notably, compound <strong>A8</strong> displayed favorable pharmacokinetic properties and efficaciously suppressed tumor growth in an NCI–H520 xenograft mouse model without observable adverse effects. These findings collectively establish compound <strong>A8</strong> as a promising candidate for the development of targeted therapies against LUSC, highlighting the therapeutic potential of NSD3 inhibition.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"289 ","pages":"Article 117388"},"PeriodicalIF":6.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401891","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 : 2025-02-12DOI: 10.1016/j.ejmech.2025.117381
Yue Xu , Hang Yang , Yunxuan Li , Yuying Qi , Fangling Zhao , Yun Hong , Binbin Cheng , Zebei Lu , Jiaming Zhang , Chunyi Guo , Jie Fu , Qinrong Lin , Chunhong Chen , Ningning Shi , Jianping Cai , Ke Li , Shuanghu Wang , Ruijuan Gao , Dapeng Dai
Translational readthrough (TR) regulation has emerged as a promising therapeutic strategy for cancer treatment. Utilizing a constructed monoclonal cell line AG-9, designed for screening compounds that induce TR, we identified a BRD4-targeted PROTAC molecule, dBET57, that promotes TR by degrading GSPT1. Notably, dBET57 exhibited significant antiproliferative activity against acute myeloid leukemia (AML) and non-Hodgkin lymphoma (NHL) cells across a diverse panel of tumor cell lines. Building on these findings, we optimized the structure of dBET57, leading to the development of analogs with enhanced dual-target degradation capabilities. Most of these optimized degraders demonstrated superior antiproliferative activity in vitro against various AML and NHL cell lines when compared to dBET57. Among them, DP-15 emerged as a particularly promising candidate, exhibiting significant anticancer activity against both AML and NHL cells while maintaining acceptable safety profiles for normal leukocytes. Furthermore, DP-15 demonstrated enhanced antitumor efficacy in mouse cell-derived xenograft (CDX) models. Our findings highlight the potential of dual BRD4 and GSPT1 degraders, such as DP-15, as effective therapeutic agents for the treatment of hematological malignancies.
{"title":"Discovery of highly potent dual GSPT1/BRD4 degraders with anti-AML activity","authors":"Yue Xu , Hang Yang , Yunxuan Li , Yuying Qi , Fangling Zhao , Yun Hong , Binbin Cheng , Zebei Lu , Jiaming Zhang , Chunyi Guo , Jie Fu , Qinrong Lin , Chunhong Chen , Ningning Shi , Jianping Cai , Ke Li , Shuanghu Wang , Ruijuan Gao , Dapeng Dai","doi":"10.1016/j.ejmech.2025.117381","DOIUrl":"10.1016/j.ejmech.2025.117381","url":null,"abstract":"<div><div>Translational readthrough (TR) regulation has emerged as a promising therapeutic strategy for cancer treatment. Utilizing a constructed monoclonal cell line AG-9, designed for screening compounds that induce TR, we identified a BRD4-targeted PROTAC molecule, dBET57, that promotes TR by degrading GSPT1. Notably, dBET57 exhibited significant antiproliferative activity against acute myeloid leukemia (AML) and non-Hodgkin lymphoma (NHL) cells across a diverse panel of tumor cell lines. Building on these findings, we optimized the structure of dBET57, leading to the development of analogs with enhanced dual-target degradation capabilities. Most of these optimized degraders demonstrated superior antiproliferative activity in vitro against various AML and NHL cell lines when compared to dBET57. Among them, DP-15 emerged as a particularly promising candidate, exhibiting significant anticancer activity against both AML and NHL cells while maintaining acceptable safety profiles for normal leukocytes. Furthermore, DP-15 demonstrated enhanced antitumor efficacy in mouse cell-derived xenograft (CDX) models. Our findings highlight the potential of dual BRD4 and GSPT1 degraders, such as DP-15, as effective therapeutic agents for the treatment of hematological malignancies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117381"},"PeriodicalIF":6.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401890","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 : 2025-02-12DOI: 10.1016/j.ejmech.2025.117389
Santo Previti , Elsa Calcaterra , Carla Di Chio , Benito Natale , Muhammad Waqas , Marta Bogacz , Tanja Schirmeister , Florine Cavelier , Maria Luisa Calabrò , Sandro Cosconati , Roberta Ettari , Maria Zappalà
In this structure-activity relationship (SAR) study, we report the development of rhodesain-targeting peptidomimetics with antitrypanosomal activity. The new compounds (SPR65-SPR80) feature the 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) moiety as conformationally constrained Phe analog. Various substituents were inserted at the P1 and P3 positions, and the methyl vinyl ketone moiety was introduced as warhead. The incorporation of Tic resulted in reduced affinity against rhodesain compared to the parent compounds containing Phe (2a-m), suggesting that its rigidity negatively affects target binding. Nevertheless, promising EC50 values ranging from 0.42 to 1.35 μM were observed in cell-based assays, probably due to better pharmacokinetic properties and/or interactions with additional protozoal targets. CC50 values > 100 μM were observed. Therefore, while Tic is less tolerated by rhodesain, its incorporation in peptidomimetic Michael acceptors led to antitrypanosomal effects that were comparable or slightly better than those of the parent compounds and no cytotoxicity up to 100 μM. These findings could be taken into consideration in future SAR studies aimed at the development of antitrypanosomal agents.
{"title":"Identification of constrained peptidomimetics carrying a Michael acceptor warhead as antitrypanosomal agents","authors":"Santo Previti , Elsa Calcaterra , Carla Di Chio , Benito Natale , Muhammad Waqas , Marta Bogacz , Tanja Schirmeister , Florine Cavelier , Maria Luisa Calabrò , Sandro Cosconati , Roberta Ettari , Maria Zappalà","doi":"10.1016/j.ejmech.2025.117389","DOIUrl":"10.1016/j.ejmech.2025.117389","url":null,"abstract":"<div><div>In this structure-activity relationship (SAR) study, we report the development of rhodesain-targeting peptidomimetics with antitrypanosomal activity. The new compounds (<strong>SPR65</strong>-<strong>SPR80</strong>) feature the 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) moiety as conformationally constrained Phe analog. Various substituents were inserted at the P1 and P3 positions, and the methyl vinyl ketone moiety was introduced as warhead. The incorporation of Tic resulted in reduced affinity against rhodesain compared to the parent compounds containing Phe (<strong>2a-m</strong>), suggesting that its rigidity negatively affects target binding. Nevertheless, promising EC<sub>50</sub> values ranging from 0.42 to 1.35 μM were observed in cell-based assays, probably due to better pharmacokinetic properties and/or interactions with additional protozoal targets. CC<sub>50</sub> values > 100 μM were observed. Therefore, while Tic is less tolerated by rhodesain, its incorporation in peptidomimetic Michael acceptors led to antitrypanosomal effects that were comparable or slightly better than those of the parent compounds and no cytotoxicity up to 100 μM. These findings could be taken into consideration in future SAR studies aimed at the development of antitrypanosomal agents.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117389"},"PeriodicalIF":6.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-12DOI: 10.1016/j.ejmech.2025.117360
Jiefu Wang , Ning Wang , Mengmeng Wang , Ning Liu , Chenyang Wang , Ning Li , Linrong Mu , Yurui Jiang , Jia Chen , Jinxiao Li , Guang Yang , Junfeng Wang , Shuangwei Liu , Kun Zhang
Acute Myeloid Leukemia (AML) is a devastating hematologic malignancy. Chemotherapy remains the primary treatment, offering rapid disease control and potential complete remission. However, more than half of the patients develop resistance and relapse, significantly reducing patient survival. Research has shown that drug-resistance and recurrence of AML are closely linked to leukemic stemness. Consequently, discovering new anti-Leukemia stem cell (LSC) compounds is a promising strategy for the treatment of AML in clinic. Additionally, the recent focus on inducing non-apoptotic programmed cell death in AML cells presents an alternative direction for therapeutic drug development, targeting current anti-apoptotic pathways. In this study, novel Sitolactone analogues, potential anti-LSCs compounds, were designed and synthesized based on the “biomimetic design” strategy. Compound 42 was found to significantly inhibit proliferation of AML cells. Subsequent biological evaluation revealed that this compound not only reduced the population of LSCs but also effectively induced PANoptosis in AML cells. Given the active compound's poor water solubility, a prodrug modification strategy was employed to enhance in vivo delivery with superior oral bioavailability and PK properties. This approach significantly suppressed AML cell growth in a mouse orthotropic model with favorable in vivo tolerance.
{"title":"Discovery of novel sitolactone derivative leading to PANoptosis and differentiation of acute myeloid leukemia cells","authors":"Jiefu Wang , Ning Wang , Mengmeng Wang , Ning Liu , Chenyang Wang , Ning Li , Linrong Mu , Yurui Jiang , Jia Chen , Jinxiao Li , Guang Yang , Junfeng Wang , Shuangwei Liu , Kun Zhang","doi":"10.1016/j.ejmech.2025.117360","DOIUrl":"10.1016/j.ejmech.2025.117360","url":null,"abstract":"<div><div>Acute Myeloid Leukemia (AML) is a devastating hematologic malignancy. Chemotherapy remains the primary treatment, offering rapid disease control and potential complete remission. However, more than half of the patients develop resistance and relapse, significantly reducing patient survival. Research has shown that drug-resistance and recurrence of AML are closely linked to leukemic stemness. Consequently, discovering new anti-Leukemia stem cell (LSC) compounds is a promising strategy for the treatment of AML in clinic. Additionally, the recent focus on inducing non-apoptotic programmed cell death in AML cells presents an alternative direction for therapeutic drug development, targeting current anti-apoptotic pathways. In this study, novel Sitolactone analogues, potential <em>anti</em>-LSCs compounds, were designed and synthesized based on the “biomimetic design” strategy. Compound <strong>42</strong> was found to significantly inhibit proliferation of AML cells. Subsequent biological evaluation revealed that this compound not only reduced the population of LSCs but also effectively induced PANoptosis in AML cells. Given the active compound's poor water solubility, a prodrug modification strategy was employed to enhance <em>in vivo</em> delivery with superior oral bioavailability and PK properties. This approach significantly suppressed AML cell growth in a mouse orthotropic model with favorable <em>in vivo</em> tolerance.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117360"},"PeriodicalIF":6.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401888","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}
The KRASG12C mutation, which occurs in approximately 14% of lung adenocarcinomas, has recently become a crucial target for therapy via small molecules that covalently bind to the mutated cysteine. In this study, a novel series of pyrrolopyrimidine derivatives was rationally designed and synthesized, employing a structure-based drug design strategy. Through structure-activity relationship (SAR) analysis, compound SK-17 emerged as a direct and highly potent inhibitor of KRASG12C. Cellular assays illustrated that SK-17 exhibits potent antiproliferative effects, induces apoptosis, possesses anti-tumor metastasis properties, and effectively inhibits the downstream KRAS pathway in a dose-dependent manner. Moreover, the synergistic enhancement observed when SK-17 is combined with SHP2 inhibitors in vitro underscores its innovative potential in combinatorial therapies. In the xenograft mouse model, SK-17 demonstrated outstanding tumor growth suppression with good safety. Importantly, the in vivo test results show that compound SK-17 has a superior PK profile and lower toxicity in zebrafish test. These results demonstrated the potential of SK-17 with novel scaffold as a promising lead compound targeting KRASG12C to guide in-depth structural optimization.
{"title":"Design, synthesis and biological evaluation of pyrrolopyrimidine urea derivatives as novel KRASG12C inhibitors for the treatment of cancer","authors":"Yanguo Shang, Miaomiao Pang, Shengnan Fu, Wenjuan Fei, Boxuan Chen, yaoyao zhang, Jinxin Wang, Tao Shen","doi":"10.1016/j.ejmech.2025.117391","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117391","url":null,"abstract":"The KRAS<sup>G12C</sup> mutation, which occurs in approximately 14% of lung adenocarcinomas, has recently become a crucial target for therapy via small molecules that covalently bind to the mutated cysteine. In this study, a novel series of pyrrolopyrimidine derivatives was rationally designed and synthesized, employing a structure-based drug design strategy. Through structure-activity relationship (SAR) analysis, compound <strong>SK-17</strong> emerged as a direct and highly potent inhibitor of KRAS<sup>G12C</sup>. Cellular assays illustrated that <strong>SK-17</strong> exhibits potent antiproliferative effects, induces apoptosis, possesses anti-tumor metastasis properties, and effectively inhibits the downstream KRAS pathway in a dose-dependent manner. Moreover, the synergistic enhancement observed when <strong>SK-17</strong> is combined with SHP2 inhibitors in vitro underscores its innovative potential in combinatorial therapies. In the xenograft mouse model, <strong>SK-17</strong> demonstrated outstanding tumor growth suppression with good safety. Importantly, the in vivo test results show that compound SK-17 has a superior PK profile and lower toxicity in zebrafish test. These results demonstrated the potential of <strong>SK-17</strong> with novel scaffold as a promising lead compound targeting KRAS<sup>G12C</sup> to guide in-depth structural optimization.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"16 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401889","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 : 2025-02-12DOI: 10.1016/j.ejmech.2025.117392
Rasha Z. Batran , Manal S. Ebaid , Sherry N. Nasralla , Ninh The Son , Nguyen Xuan Ha , Hoda Atef Abdelsattar Ibrahim , Mahmoud Abdelrahman Alkabbani , Yusuke Kasai , Hiroshi Imagawa , Mohammad M. Al-Sanea , Tamer M. Ibrahim , Abdelsamed I. Elshamy , Adnan A. Bekhit , Wagdy M. Eldehna , Ahmed Sabt
Leishmaniasis, recognized as a neglected tropical disease, is a major global health issue that impacts millions of individuals across the globe. The limitations of existing treatments underscore the urgent need for novel antileishmanial drugs. In response, this study synthesized and evaluated fifteen hybrid compounds (7a-c, 10a-j, and 13a-b) combining 4-hydroxycoumarin and pyrazolyl indolin-2-one motifs for their in vitro antileishmanial efficacy towards Leishmania major. These molecules demonstrated remarkable activity against the promastigote form, with IC50 values ranging from 1.21 to 7.21 μM, surpassing the reference drug miltefosine (IC50 = 7.83 μM). Assessment against the intracellular amastigote form revealed efficient inhibitory action (IC50: 2.41–9.44 μM vs. 8.07 μM for miltefosine). Compounds 7a and 7b exhibited exceptional antileishmanial activity against both forms while maintaining favorable safety profiles. Mechanistic studies indicated that the most effective compounds act through an antifolate mechanism, targeting pteridine reductase 1 (PTR1) and dihydrofolate reductase-thymidylate synthase (DHFR-TS). Molecular docking and dynamics simulations of compounds 7a and 7b revealed strong in-silico binding and stable dynamics against PTR1, suggesting a high potential for enzyme inhibition. These findings present a promising new class of antileishmanial agents targeting the folate pathway.
{"title":"Synthesis and mechanistic insights of Coumarinyl-Indolinone hybrids as potent inhibitors of Leishmania major","authors":"Rasha Z. Batran , Manal S. Ebaid , Sherry N. Nasralla , Ninh The Son , Nguyen Xuan Ha , Hoda Atef Abdelsattar Ibrahim , Mahmoud Abdelrahman Alkabbani , Yusuke Kasai , Hiroshi Imagawa , Mohammad M. Al-Sanea , Tamer M. Ibrahim , Abdelsamed I. Elshamy , Adnan A. Bekhit , Wagdy M. Eldehna , Ahmed Sabt","doi":"10.1016/j.ejmech.2025.117392","DOIUrl":"10.1016/j.ejmech.2025.117392","url":null,"abstract":"<div><div>Leishmaniasis, recognized as a neglected tropical disease, is a major global health issue that impacts millions of individuals across the globe. The limitations of existing treatments underscore the urgent need for novel antileishmanial drugs. In response, this study synthesized and evaluated fifteen hybrid compounds (<strong>7a-c</strong>, <strong>10a-j</strong>, and <strong>13a-b</strong>) combining 4-hydroxycoumarin and pyrazolyl indolin-2-one motifs for their <em>in vitro</em> antileishmanial efficacy towards <em>Leishmania major</em>. These molecules demonstrated remarkable activity against the promastigote form, with IC<sub>50</sub> values ranging from 1.21 to 7.21 μM, surpassing the reference drug miltefosine (IC<sub>50</sub> = 7.83 μM). Assessment against the intracellular amastigote form revealed efficient inhibitory action (IC<sub>50</sub>: 2.41–9.44 μM vs. 8.07 μM for miltefosine). Compounds <strong>7a</strong> and <strong>7b</strong> exhibited exceptional antileishmanial activity against both forms while maintaining favorable safety profiles. Mechanistic studies indicated that the most effective compounds act through an antifolate mechanism, targeting pteridine reductase 1 (PTR1) and dihydrofolate reductase-thymidylate synthase (DHFR-TS). Molecular docking and dynamics simulations of compounds <strong>7a</strong> and <strong>7b</strong> revealed strong in-silico binding and stable dynamics against PTR1, suggesting a high potential for enzyme inhibition. These findings present a promising new class of antileishmanial agents targeting the folate pathway.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117392"},"PeriodicalIF":6.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393993","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}
Epstein-Barr virus (EBV) is the first identified oncogenic virus. It causes three types of diseases: lymphomas, carcinomas, and autoimmune diseases. It is estimated that two hundred thousand deaths are due to EBV each year. After a primary infection, EBV can remain latent lifelong. Reactivation to lytic phase can be induced by various drugs including small organic molecules, biologics, or a combination of both. In this review, we identified the most relevant results obtained with small organic compounds against Epstein-Barr virus-associated diseases. Specific treatments targeting Epstein-Barr Nuclear Antigen 1 are emerging concerning small organic molecules and showed promising results against several EBV-related malignancies.
{"title":"Emerging drugs for Epstein-Barr virus associated-diseases","authors":"Nassima Oumata , Qian Zhong , Yongmin Zhang , Hervé Galons , Graciela Andrei , Musheng Zeng","doi":"10.1016/j.ejmech.2025.117386","DOIUrl":"10.1016/j.ejmech.2025.117386","url":null,"abstract":"<div><div>Epstein-Barr virus (EBV) is the first identified oncogenic virus. It causes three types of diseases: lymphomas, carcinomas, and autoimmune diseases. It is estimated that two hundred thousand deaths are due to EBV each year. After a primary infection, EBV can remain latent lifelong. Reactivation to lytic phase can be induced by various drugs including small organic molecules, biologics, or a combination of both. In this review, we identified the most relevant results obtained with small organic compounds against Epstein-Barr virus-associated diseases. Specific treatments targeting Epstein-Barr Nuclear Antigen 1 are emerging concerning small organic molecules and showed promising results against several EBV-related malignancies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"287 ","pages":"Article 117386"},"PeriodicalIF":6.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143385347","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 : 2025-02-10DOI: 10.1016/j.ejmech.2025.117378
Meng Xia , Ziteng Li , Hanrui Jiang , Yuanqing Li , Linghao Hu , Yongchang He , Siqi Huang , Lei Tang , Cheng Luo , Shuangxi Gu , Hong Ding , Mingliang Wang
Triple-negative breast cancer (TNBC) is widely recognized as the most aggressive subtype of breast cancer, and treatment options for patients with TNBC remain highly limited. Recently, cyclin-dependent kinases 12/13 (CDK12/13) have been identified as promising therapeutic targets for TNBC. In our study, we report the design and synthesis of novel imidazo[1,2-b]pyrazine-based covalent inhibitors of CDK12/13, which exhibit potent inhibitory activity against TNBC cells. Among these compounds, compound 24 emerged as the most potent inhibitor, with CDK12 IC50 of 15.5 nM and CDK13 IC50 of 12.2 nM. Compound 24 forms a covalent bond with Cys1039 of CDK12 and effectively suppresses the proliferation of TNBC cell lines MDA-MB-231 and MDA-MB-468, with EC50 values of 5.0 nM and 6.0 nM, respectively. Compound 24 demonstrated superior efficacy to the currently known CDK12/13 covalent inhibitor, THZ531. These findings suggest compound 24 may be a promising lead for developing CDK12/13-targeted therapies for treating TNBC.
{"title":"Discovery of novel imidazo[1,2-b]pyridazine derivatives as potent covalent inhibitors of CDK12/13","authors":"Meng Xia , Ziteng Li , Hanrui Jiang , Yuanqing Li , Linghao Hu , Yongchang He , Siqi Huang , Lei Tang , Cheng Luo , Shuangxi Gu , Hong Ding , Mingliang Wang","doi":"10.1016/j.ejmech.2025.117378","DOIUrl":"10.1016/j.ejmech.2025.117378","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is widely recognized as the most aggressive subtype of breast cancer, and treatment options for patients with TNBC remain highly limited. Recently, cyclin-dependent kinases 12/13 (CDK12/13) have been identified as promising therapeutic targets for TNBC. In our study, we report the design and synthesis of novel imidazo[1,2-<em>b</em>]pyrazine-based covalent inhibitors of CDK12/13, which exhibit potent inhibitory activity against TNBC cells. Among these compounds, compound <strong>24</strong> emerged as the most potent inhibitor, with CDK12 IC<sub>50</sub> of 15.5 nM and CDK13 IC<sub>50</sub> of 12.2 nM. Compound <strong>24</strong> forms a covalent bond with Cys1039 of CDK12 and effectively suppresses the proliferation of TNBC cell lines MDA-MB-231 and MDA-MB-468, with EC<sub>50</sub> values of 5.0 nM and 6.0 nM, respectively. Compound <strong>24</strong> demonstrated superior efficacy to the currently known CDK12/13 covalent inhibitor, THZ531. These findings suggest compound <strong>24</strong> may be a promising lead for developing CDK12/13-targeted therapies for treating TNBC.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"288 ","pages":"Article 117378"},"PeriodicalIF":6.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375230","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 : 2025-02-09DOI: 10.1016/j.ejmech.2025.117380
Saghir Ali, Xiaochen Tian, Salvatore A. Meccia, Jia Zhou
This comprehensive review offers an update on the FDA-approved halogen-containing drugs in 2024. The agency approved a total of 50 drugs, including small molecules and macromolecules. Excitingly, 16 out of 50 are halogen-containing drugs, indicated to diagnose, mitigate and treat the various human diseases. Among halogens, fluorine and chlorine are highly prevalent in drug discovery and development. Therefore, the properties of fluorine and chlorine and their impact on the drug profile are briefly discussed. In addition, the specific role of halogens in these drugs has been discussed with the help of structure-activity relationships (SARs), co-crystal structures, and closely related literature precedents. This review also provides the additional information for each drug, such as trade name, active ingredients, route of administration, approval date, sponsors, indication, mode of action, major drug metabolizing enzyme(s), and route of elimination. We expect that the present review may garner the attention of drug discovery researchers and inspire them toward the potential applications of halogens to discover novel therapeutics in the future.
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