Pub Date : 2026-01-12DOI: 10.1016/j.ejmech.2026.118569
Wanwan Zhang , Jinfeng Wen , Yuanyuan Wu , Yong Xuan , Qiangqiang Han , Xi Chen , Jingtian Yu , Haijun Yu , Baishan Jiang
Dysregulation of the cell cycle, a hallmark of cancer, frequently involves aberrant activation of cyclin D-CDK4/6 complexes. Although dual-CDK4/6 inhibitors are effective in advanced hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer, CDK6 is preferentially expressed and functionally upregulated in hematologic malignancies, making it a promising therapeutic target. The high structural homology between CDK4 and CDK6, however, has made developing selective CDK6 inhibitors exceptionally difficult. Herein, we report the design and synthesis of a novel series of CDK6 degraders based on a CDK2/4/6 inhibitor. This investigation led to the discovery of a CDK6 degrader WWZ-11–098. WWZ-11–098 induced pronounced CDK6 degradation (DC50 = 2.6 nM and Dmax >99 %) in a Cereblon (CRBN)-dependent manner, while sparing CDK1, CDK2, CDK4, and CDK9. Moreover, WWZ-11–098 exhibited potent antiproliferation activity (MOLT-4: IC50 = 70 nM) by inducing G1-S cell cycle arrest. In addition, WWZ-11–098 displayed favorable pharmacokinetic properties (Cmax = 11833 ng/mL, T1/2 = 2.64 h after a 5 mpk IV dose) and exhibited robust antitumor efficacy (TGI: 77.1 % @10 mpk) in a MOLT-4 xenograft model without signs of toxicity. The compound provides not only a valuable chemical probe but also a lead structure for further development of CDK6 degraders.
{"title":"Discovery of WWZ-11-098: a rigid and selective CDK6 degrader","authors":"Wanwan Zhang , Jinfeng Wen , Yuanyuan Wu , Yong Xuan , Qiangqiang Han , Xi Chen , Jingtian Yu , Haijun Yu , Baishan Jiang","doi":"10.1016/j.ejmech.2026.118569","DOIUrl":"10.1016/j.ejmech.2026.118569","url":null,"abstract":"<div><div>Dysregulation of the cell cycle, a hallmark of cancer, frequently involves aberrant activation of cyclin D-CDK4/6 complexes. Although dual-CDK4/6 inhibitors are effective in advanced hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer, CDK6 is preferentially expressed and functionally upregulated in hematologic malignancies, making it a promising therapeutic target. The high structural homology between CDK4 and CDK6, however, has made developing selective CDK6 inhibitors exceptionally difficult. Herein, we report the design and synthesis of a novel series of CDK6 degraders based on a CDK2/4/6 inhibitor. This investigation led to the discovery of a CDK6 degrader <strong>WWZ-11</strong>–<strong>098</strong>. <strong>WWZ-11</strong>–<strong>098</strong> induced pronounced CDK6 degradation (DC<sub>50</sub> = 2.6 nM and D<sub>max</sub> >99 %) in a Cereblon (CRBN)-dependent manner, while sparing CDK1, CDK2, CDK4, and CDK9. Moreover, <strong>WWZ-11</strong>–<strong>098</strong> exhibited potent antiproliferation activity (MOLT-4: IC<sub>50</sub> = 70 nM) by inducing G1-S cell cycle arrest. In addition, <strong>WWZ-11</strong>–<strong>098</strong> displayed favorable pharmacokinetic properties (C<sub>max</sub> = 11833 ng/mL, T<sub>1/2</sub> = 2.64 h after a 5 mpk IV dose) and exhibited robust antitumor efficacy (TGI: 77.1 % @10 mpk) in a MOLT-4 xenograft model without signs of toxicity. The compound provides not only a valuable chemical probe but also a lead structure for further development of CDK6 degraders.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118569"},"PeriodicalIF":5.9,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956874","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 : 2026-01-10DOI: 10.1016/j.ejmech.2026.118562
Rui-Chen Liu , Jue-Ru Zhang , Cong-Xuan Ma , Wen-Tian Liu , Si-Xi Wang , Si-Meng Liu , Yun Li , Yi-Lan Li , Jing Ding , Li-Fan Guo , Ming-Jia Yu , Jian-Hua Liang
Macrolide antibiotics are classical protein synthesis inhibitors. However, the frequent development of clinical resistance significantly limits their utility. We report a novel series of ketolide-quinolone hybrids (26–31) that uniquely disrupt both protein synthesis and DNA replication. The new lead 26l exhibited balanced dual inhibition with IC50 values of 1.11 μM against ribosomes and 3.31 μM against DNA gyrases. In vivo mechanistic studies, including resistance mutation mapping in E. coli SQ110DTC strains and MIC profiling against ribosome- or/and gyrase-mutated E. coli SQ110DTC, confirmed concurrent target engagement of 26l. This bifunctional activity not only restored in vitro efficacy against macrolide-resistant erm-mediated resistant Gram-positive pathogens (S. pneumoniae and S. pyogenes), but also significantly enhanced activity against Gram-negative H. influenzae and M. catarrhalis. Notably, compound 26l demonstrated reduced CYP3A4 inhibition—a common side effect associated with macrolide antibiotics—compared to telithromycin. Compound 26l exhibited good stability in both mouse plasma and liver microsomes. Molecular docking studies elucidated how the hybrid simultaneously occupies two key bacterial targets—the ribosome and DNA gyrase—through specific interactions mediated by its macrolide core and quinolone moiety. With its dual-targeting mechanism, expanded spectrum coverage, and optimized safety properties, the new lead 26l emerges as a strategic solution to the escalating crisis of macrolide resistance in community-acquired bacterial pneumonia.
{"title":"Dual-targeting ketolide-quinolone hybrids overcome erm-mediated resistant pathogens via ribosomal and DNA gyrase inhibition","authors":"Rui-Chen Liu , Jue-Ru Zhang , Cong-Xuan Ma , Wen-Tian Liu , Si-Xi Wang , Si-Meng Liu , Yun Li , Yi-Lan Li , Jing Ding , Li-Fan Guo , Ming-Jia Yu , Jian-Hua Liang","doi":"10.1016/j.ejmech.2026.118562","DOIUrl":"10.1016/j.ejmech.2026.118562","url":null,"abstract":"<div><div>Macrolide antibiotics are classical protein synthesis inhibitors. However, the frequent development of clinical resistance significantly limits their utility. We report a novel series of ketolide-quinolone hybrids (<strong>26</strong>–<strong>31</strong>) that uniquely disrupt both protein synthesis and DNA replication. The new lead <strong>26l</strong> exhibited balanced dual inhibition with IC<sub>50</sub> values of 1.11 μM against ribosomes and 3.31 μM against DNA gyrases. <em>In vivo</em> mechanistic studies, including resistance mutation mapping in <em>E. coli</em> SQ110DTC strains and MIC profiling against ribosome- or/and gyrase-mutated <em>E. coli</em> SQ110DTC, confirmed concurrent target engagement of <strong>26l</strong>. This bifunctional activity not only restored <em>in vitro</em> efficacy against macrolide-resistant erm-mediated resistant Gram-positive pathogens (<em>S. pneumoniae</em> and <em>S. pyogenes</em>), but also significantly enhanced activity against Gram-negative <em>H. influenzae</em> and <em>M. catarrhalis</em>. Notably, compound <strong>26l</strong> demonstrated reduced CYP3A4 inhibition—a common side effect associated with macrolide antibiotics—compared to telithromycin. Compound <strong>26l</strong> exhibited good stability in both mouse plasma and liver microsomes. Molecular docking studies elucidated how the hybrid simultaneously occupies two key bacterial targets—the ribosome and DNA gyrase—through specific interactions mediated by its macrolide core and quinolone moiety. With its dual-targeting mechanism, expanded spectrum coverage, and optimized safety properties, the new lead <strong>26l</strong> emerges as a strategic solution to the escalating crisis of macrolide resistance in community-acquired bacterial pneumonia.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118562"},"PeriodicalIF":5.9,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956881","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 : 2026-01-09DOI: 10.1016/j.ejmech.2026.118577
Wanjia Liu , Yimin Chen , Zehua Li , Mengchao Cui
Clear-cell renal cell carcinoma (ccRCC) represents the predominant histological subtype of renal carcinoma and accounts for the majority of kidney cancer-related deaths. Conventional [18F]FDG PET frequently fails to detect ccRCC because of its intrinsically low glucose metabolism. Carbonic anhydrase IX (CAIX), a hypoxia-inducible, tumor-specific cell-surface enzyme that is highly expressed in nearly all ccRCCs but absent from healthy kidney tissue, represents an attractive alternative target. Here, we developed a panel of modularly designed 68Ga-labeled acetazolamide analogues incorporating varied linkers and chelators. Among these, [68Ga]Ga-14 demonstrated the most favorable overall profile, including high stability and optimized pharmacokinetics. [68Ga]Ga-14 bound recombinant human CAIX with high affinity (IC50 = 61 ± 9.5 nM). In OS-RC-2 xenograft models, it achieved superior tumor uptake (SUVmax = 1.41 ± 0.04) and tumor-to-muscle ratio (9.68) at 1 h post-injection. Despite gradual tumor washout, rapid clearance from non-target tissues increased the tumor-to-muscle ratio to 14.92 at 2 h. CAIX specificity was validated by a blocking study in which excess inhibitor reduced tumor uptake by 95 %. These findings identify [68Ga]Ga-14 as a highly promising CAIX-targeted PET tracer for sensitive detection of ccRCC, with potential for future theranostic applications.
{"title":"Preclinical evaluation of 68Ga-labeled acetazolamide derivatives as radiotracers targeting carbonic anhydrase IX in clear cell renal cell carcinoma","authors":"Wanjia Liu , Yimin Chen , Zehua Li , Mengchao Cui","doi":"10.1016/j.ejmech.2026.118577","DOIUrl":"10.1016/j.ejmech.2026.118577","url":null,"abstract":"<div><div>Clear-cell renal cell carcinoma (ccRCC) represents the predominant histological subtype of renal carcinoma and accounts for the majority of kidney cancer-related deaths. Conventional [<sup>18</sup>F]<strong>FDG</strong> PET frequently fails to detect ccRCC because of its intrinsically low glucose metabolism. Carbonic anhydrase IX (CAIX), a hypoxia-inducible, tumor-specific cell-surface enzyme that is highly expressed in nearly all ccRCCs but absent from healthy kidney tissue, represents an attractive alternative target. Here, we developed a panel of modularly designed <sup>68</sup>Ga-labeled acetazolamide analogues incorporating varied linkers and chelators. Among these, [<sup>68</sup>Ga]Ga-<strong>14</strong> demonstrated the most favorable overall profile, including high stability and optimized pharmacokinetics. [<sup>68</sup>Ga]Ga-<strong>14</strong> bound recombinant human CAIX with high affinity (IC<sub>50</sub> = 61 ± 9.5 nM). In OS-RC-2 xenograft models, it achieved superior tumor uptake (SUV<sub>max</sub> = 1.41 ± 0.04) and tumor-to-muscle ratio (9.68) at 1 h post-injection. Despite gradual tumor washout, rapid clearance from non-target tissues increased the tumor-to-muscle ratio to 14.92 at 2 h. CAIX specificity was validated by a blocking study in which excess inhibitor reduced tumor uptake by 95 %. These findings identify [<sup>68</sup>Ga]Ga-<strong>14</strong> as a highly promising CAIX-targeted PET tracer for sensitive detection of ccRCC, with potential for future theranostic applications.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118577"},"PeriodicalIF":5.9,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949947","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 : 2026-01-09DOI: 10.1016/j.ejmech.2026.118576
François Sindt, Didier Rognan
On-demand chemical spaces consist of molecules that are, a priori, readily synthesizable from sets of commercial building blocks through robust organic reactions. As these spaces expand—now reaching the scale of several trillions of compounds—computational chemists are compelled to develop innovative algorithms for efficient enumeration, storage, and virtual screening, particularly when three-dimensional constraints of target proteins are involved. This review examines the primary approaches to structure-based ultra-large virtual screening, highlighting the significant advantages of screening at such a scale while addressing the remaining practical and theoretical hurdles. Current prospective applications, often relying on brute-force docking, typically report improved hit rates and more potent primary hits; however, they must contend with the exponential growth of available chemical space. To address this, recent developments have integrated active learning, probabilistic sampling, and synthon-guided methods to accelerate docking and prioritize the most promising compounds. Finally, we provide a perspective on the transformative impact of ultra-large chemical spaces on early hit identification and the overall organization of early drug discovery.
{"title":"Structure-based virtual screening of ultra-large chemical spaces: Advances and pitfalls","authors":"François Sindt, Didier Rognan","doi":"10.1016/j.ejmech.2026.118576","DOIUrl":"10.1016/j.ejmech.2026.118576","url":null,"abstract":"<div><div>On-demand chemical spaces consist of molecules that are, <em>a priori</em>, readily synthesizable from sets of commercial building blocks through robust organic reactions. As these spaces expand—now reaching the scale of several trillions of compounds—computational chemists are compelled to develop innovative algorithms for efficient enumeration, storage, and virtual screening, particularly when three-dimensional constraints of target proteins are involved. This review examines the primary approaches to structure-based ultra-large virtual screening, highlighting the significant advantages of screening at such a scale while addressing the remaining practical and theoretical hurdles. Current prospective applications, often relying on brute-force docking, typically report improved hit rates and more potent primary hits; however, they must contend with the exponential growth of available chemical space. To address this, recent developments have integrated active learning, probabilistic sampling, and synthon-guided methods to accelerate docking and prioritize the most promising compounds. Finally, we provide a perspective on the transformative impact of ultra-large chemical spaces on early hit identification and the overall organization of early drug discovery.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118576"},"PeriodicalIF":5.9,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145947734","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 : 2026-01-09DOI: 10.1016/j.ejmech.2026.118574
Fansheng Ran , Rong Cao , Yifan Ma , Dongliang Ji , Tiantian Sun , Mingming Chang , Chen Chen , Chunyu Yin , Hongming Huang , Yong Ling
The constitutive activation of FMS-like tyrosine kinase 3 (FLT3) is closely associated with the progression of hematologic malignancies; however, the clinical application of FLT3 inhibitors has been limited by acquired drug resistance. Recent advances in epigenetic regulatory mechanisms revealed that aberrant histone deacetylase (HDAC) expression exacerbates resistance to FLT3 inhibitors through multiple signaling pathways. Accordingly, we designed and synthesized a series of aminopyrimidine-hydroxamate derivatives (6a-6s) as dual FLT3/HDAC inhibitors for the treatment of hematologic malignancies. The representative compound 6s demonstrates superior dual-targeting properties, exhibiting 150-fold higher FLT3 inhibition (half-maximal inhibitory concentration (IC50) = 14 nM) compared with the reference drug tandutinib (IC50 = 2098 nM) and 2.9-fold higher HDAC1 inhibition (IC50 = 27 nM) relative to vorinostat (SAHA; IC50 = 79 nM). In the human acute myeloid leukemia MV-4-11 cell line, 6s exhibits remarkable antiproliferative potency (IC50 = 29 nM), outperforming the single-target inhibitors tandutinib (IC50 = 7630 nM) and SAHA (IC50 = 3760 nM) by 263- and 129-folds, respectively. Notably, 6s shows marked efficacy in a human mantle cell lymphoma Jeko-1 model (IC50 = 99 nM), indicating broad-spectrum therapeutic potential. Furthermore, 6s exhibits remarkable kinase selectivity, plasma stability, and human hepatic microsomal metabolic stability. Importantly, in the Jeko-1 xenograft model, 6s achieves 53.34 % tumor growth inhibition at a dose of 30 mg/kg with no observable toxicity. Collectively, these results indicate that 6s is a potent dual FLT3/HDAC inhibitor with promising therapeutic potential for hematologic malignancies.
{"title":"Discovery of novel aminopyrimidine-hydroxamate derivatives as dual FLT3/HDAC inhibitors: Design, synthesis, and anti-hematologic malignancy evaluation","authors":"Fansheng Ran , Rong Cao , Yifan Ma , Dongliang Ji , Tiantian Sun , Mingming Chang , Chen Chen , Chunyu Yin , Hongming Huang , Yong Ling","doi":"10.1016/j.ejmech.2026.118574","DOIUrl":"10.1016/j.ejmech.2026.118574","url":null,"abstract":"<div><div>The constitutive activation of FMS-like tyrosine kinase 3 (FLT3) is closely associated with the progression of hematologic malignancies; however, the clinical application of FLT3 inhibitors has been limited by acquired drug resistance. Recent advances in epigenetic regulatory mechanisms revealed that aberrant histone deacetylase (HDAC) expression exacerbates resistance to FLT3 inhibitors through multiple signaling pathways. Accordingly, we designed and synthesized a series of aminopyrimidine-hydroxamate derivatives (<strong>6a-6s</strong>) as dual FLT3/HDAC inhibitors for the treatment of hematologic malignancies. The representative compound <strong>6s</strong> demonstrates superior dual-targeting properties, exhibiting 150-fold higher FLT3 inhibition (half-maximal inhibitory concentration (IC<sub>50</sub>) = 14 nM) compared with the reference drug tandutinib (IC<sub>50</sub> = 2098 nM) and 2.9-fold higher HDAC1 inhibition (IC<sub>50</sub> = 27 nM) relative to vorinostat (SAHA; IC<sub>50</sub> = 79 nM). In the human acute myeloid leukemia MV-4-11 cell line, <strong>6s</strong> exhibits remarkable antiproliferative potency (IC<sub>50</sub> = 29 nM), outperforming the single-target inhibitors tandutinib (IC<sub>50</sub> = 7630 nM) and SAHA (IC<sub>50</sub> = 3760 nM) by 263- and 129-folds, respectively. Notably, <strong>6s</strong> shows marked efficacy in a human mantle cell lymphoma Jeko-1 model (IC<sub>50</sub> = 99 nM), indicating broad-spectrum therapeutic potential. Furthermore, <strong>6s</strong> exhibits remarkable kinase selectivity, plasma stability, and human hepatic microsomal metabolic stability. Importantly, in the Jeko-1 xenograft model, <strong>6s</strong> achieves 53.34 % tumor growth inhibition at a dose of 30 mg/kg with no observable toxicity. Collectively, these results indicate that <strong>6s</strong> is a potent dual FLT3/HDAC inhibitor with promising therapeutic potential for hematologic malignancies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118574"},"PeriodicalIF":5.9,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956887","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 : 2026-01-09DOI: 10.1016/j.ejmech.2026.118564
Wenrun Zhu , Jun Huang , Xiaoyi Deng , Yichuan Chen , Lianbao Ye , Shuang Tian , Lin Zhou , Jiang Weng , Yunjun Liu
Bisindolylmethane (BIM) is an important alkaloid derived from cruciferous plants that exhibits anti-cancer biological activity. Molecules with a BIM skeleton have long been widely recognized by medicinal chemists. Unfortunately, due to limitations in synthetic methods, research on this skeleton has mainly focused on symmetrical 3,3′-bisindolylmethane derivatives (3,3′-BIMs), wherein the two indole rings possess identical structures. In contrast, research on unsymmetrical 3,3′-BIMs has progressed slowly. Meanwhile, trifluoromethyl is a widely used “star group” in drug design due to its ability to improve pharmacological and pharmaceutical properties. To discover novel BIMs with significant anti-cancer potential and to study the variety of their structures, we designed and synthesized a series of unsymmetrical trifluoromethyl-containing BIMs based on previously reported SN1-type dehydrative nucleophilic substitution by our group. These novel BIMs inhibit various cancer cells, especially lung cancer cells A549. Among them, the compound 5b effectively induces endoplasmic reticulum stress (ERS) and leads to apoptosis, demonstrating outstanding anti-non-small cell lung cancer (NSCLC) effects in vitro and in vivo, and was significantly more effective than the BIM group. The IC50 values of BIM and 5b against A549 cells are 54.76 ± 4.7 μM and 3.88 ± 0.1 μM, respectively. Specifically, anti-tumor activity assays in vivo found the inhibitory rates of 34.80 % for BIM and 80.32 % for 5b. Hematoxylin-eosin (H&E) results showed that 5b does not cause chronic organ damage. Clearly, 5b greatly enhances anti-cancer efficacy, effectively restraining cell colonies and proliferation in the S phase. Additionally, 5b increases the content of reactive oxygen species (ROS), causing a decline in the mitochondrial membrane potential and promoting Ca2+ release. Further studies on the mechanism revealed that 5b induces ERS by activating the PERK-elF2α-CHOP signaling pathway, which could further regulate caspase and Bcl-2 family proteins, leading to apoptosis. These results demonstrate that 5b may be potent anticancer candidates for A549 tumor.
{"title":"Design, synthesis, and evaluation of unsymmetrical trifluoromethyl-containing bisindolylmethane derivatives inducing endoplasmic reticulum stress in human lung adenocarcinoma","authors":"Wenrun Zhu , Jun Huang , Xiaoyi Deng , Yichuan Chen , Lianbao Ye , Shuang Tian , Lin Zhou , Jiang Weng , Yunjun Liu","doi":"10.1016/j.ejmech.2026.118564","DOIUrl":"10.1016/j.ejmech.2026.118564","url":null,"abstract":"<div><div>Bisindolylmethane (<strong>BIM</strong>) is an important alkaloid derived from cruciferous plants that exhibits anti-cancer biological activity. Molecules with a <strong>BIM</strong> skeleton have long been widely recognized by medicinal chemists. Unfortunately, due to limitations in synthetic methods, research on this skeleton has mainly focused on symmetrical 3,3′-bisindolylmethane derivatives (3,3′-<strong>BIMs</strong>), wherein the two indole rings possess identical structures. In contrast, research on unsymmetrical 3,3′-<strong>BIMs</strong> has progressed slowly. Meanwhile, trifluoromethyl is a widely used “star group” in drug design due to its ability to improve pharmacological and pharmaceutical properties. To discover novel <strong>BIMs</strong> with significant anti-cancer potential and to study the variety of their structures, we designed and synthesized a series of unsymmetrical trifluoromethyl-containing <strong>BIMs</strong> based on previously reported S<sub>N</sub>1-type dehydrative nucleophilic substitution by our group. These novel <strong>BIMs</strong> inhibit various cancer cells, especially lung cancer cells A549. Among them, the compound <strong>5b</strong> effectively induces endoplasmic reticulum stress (ERS) and leads to apoptosis, demonstrating outstanding anti-non-small cell lung cancer (NSCLC) effects in vitro and in vivo, and was significantly more effective than the <strong>BIM</strong> group. The IC<sub>50</sub> values of <strong>BIM</strong> and <strong>5b</strong> against A549 cells are 54.76 ± 4.7 μM and 3.88 ± 0.1 μM, respectively. Specifically, anti-tumor activity assays in vivo found the inhibitory rates of 34.80 % for <strong>BIM</strong> and 80.32 % for <strong>5b</strong>. Hematoxylin-eosin (H&E) results showed that <strong>5b</strong> does not cause chronic organ damage. Clearly, <strong>5b</strong> greatly enhances anti-cancer efficacy, effectively restraining cell colonies and proliferation in the S phase. Additionally, <strong>5b</strong> increases the content of reactive oxygen species (ROS), causing a decline in the mitochondrial membrane potential and promoting Ca<sup>2+</sup> release. Further studies on the mechanism revealed that <strong>5b</strong> induces ERS by activating the PERK-elF2α-CHOP signaling pathway, which could further regulate caspase and Bcl-2 family proteins, leading to apoptosis. These results demonstrate that <strong>5b</strong> may be potent anticancer candidates for A549 tumor.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118564"},"PeriodicalIF":5.9,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145947735","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 : 2026-01-09DOI: 10.1016/j.ejmech.2026.118571
Tianyang Zhou , Yibo Gao , Bohan Ma, Chi Wang, Shan Xu, Xiaoyu Feng, Bin Wang, Yanlin Jian, Lei Li
Proteolysis-targeting chimeras (PROTACs) have emerged as a transformative strategy for targeted protein degradation, yet their clinical translation is hindered by systemic toxicity and poor tumor selectivity, leading to dose-limiting side effects. To overcome these limitations, we designed a multi-stimuli-responsive prodrug that enables tumor-selective activation of PROTACs in response to elevated reactive oxygen species (ROS) and glutathione (GSH) in the tumor microenvironment. By masking the hydroxyl group of the VHL ligand with a ROS/GSH-cleavable thioether-urea linker, we developed a PROTAC prodrug that responds to 1O2, HOCl, H2O2, and GSH–key mediators of oxidative stress in tumors. This proof-of-concept was verified by caging BRD4 and AR PROTAC with a methylene blue fluorophore to yield NZ-BRD and NZ-AR. Upon encountering tumor-associated stimuli, these prodrugs underwent efficient activation, releasing functional PROTACs that selectively degraded BRD4 and AR in prostate cancer cells. Intriguingly, the methylene blue liberated during activation served as a self-amplifying photosensitizer, creating a positive feedback loop that boosted 1O2 generation and further enhanced prodrug cleavage. The synergistic effect between PROTAC-mediated protein degradation and photodynamic therapy led to superior antitumor efficacy of PROTAC prodrugs in vitro and in vivo. Our work establishes a spatiotemporally controlled drug activation paradigm that combines precision protein degradation with ROS-amplified activation, presenting a promising approach to mitigate the systemic toxicity associated with conventional PROTAC therapy.
{"title":"Multi-stimuli activated PROTAC prodrug for controlled protein degradation with enhanced therapeutic effects","authors":"Tianyang Zhou , Yibo Gao , Bohan Ma, Chi Wang, Shan Xu, Xiaoyu Feng, Bin Wang, Yanlin Jian, Lei Li","doi":"10.1016/j.ejmech.2026.118571","DOIUrl":"10.1016/j.ejmech.2026.118571","url":null,"abstract":"<div><div>Proteolysis-targeting chimeras (PROTACs) have emerged as a transformative strategy for targeted protein degradation, yet their clinical translation is hindered by systemic toxicity and poor tumor selectivity, leading to dose-limiting side effects. To overcome these limitations, we designed a multi-stimuli-responsive prodrug that enables tumor-selective activation of PROTACs in response to elevated reactive oxygen species (ROS) and glutathione (GSH) in the tumor microenvironment. By masking the hydroxyl group of the VHL ligand with a ROS/GSH-cleavable thioether-urea linker, we developed a PROTAC prodrug that responds to <sup>1</sup>O<sub>2</sub>, HOCl, H<sub>2</sub>O<sub>2</sub>, and GSH–key mediators of oxidative stress in tumors. This proof-of-concept was verified by caging BRD4 and AR PROTAC with a methylene blue fluorophore to yield NZ-BRD and NZ-AR. Upon encountering tumor-associated stimuli, these prodrugs underwent efficient activation, releasing functional PROTACs that selectively degraded BRD4 and AR in prostate cancer cells. Intriguingly, the methylene blue liberated during activation served as a self-amplifying photosensitizer, creating a positive feedback loop that boosted <sup>1</sup>O<sub>2</sub> generation and further enhanced prodrug cleavage. The synergistic effect between PROTAC-mediated protein degradation and photodynamic therapy led to superior antitumor efficacy of PROTAC prodrugs <em>in vitro</em> and <em>in vivo.</em> Our work establishes a spatiotemporally controlled drug activation paradigm that combines precision protein degradation with ROS-amplified activation, presenting a promising approach to mitigate the systemic toxicity associated with conventional PROTAC therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118571"},"PeriodicalIF":5.9,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145920570","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 : 2026-01-09DOI: 10.1016/j.ejmech.2026.118557
Gang Li , Xudong Qian , Yan Geng , Jun Wang , Jiaxin Chen , Yanghui Ou , Cheng Chen , Yuchuan Zhong , Wei Pan , Nan Hao , Jiaxin Huang , Guoqin Wu , Qi Zhou , Yali Zhang , Liyan Song , Shuirong Chen , Lianbao Ye , Wen-Hua Chen , Hongliang Yao
Liver injury represents a serious and potentially life-threatening medical condition. Currently, there are no sufficiently targeted or highly effective therapeutic interventions available. Herein, a new series of dual PDE3/4 inhibitors was designed and synthesized for the treatment of liver injury. Among them, compound D5 exhibited IC50 values of 10 and 9.4 nM against PDE3A and PDE4B, respectively, and inhibited the pro-inflammatory factor IL-6 (IC50 = 14.89 μM). In both cholestatic and sepsis–induced liver disease mice models, D5 significantly reduced the expression levels of inflammatory markers in liver tissue and attenuated fibrosis, thereby limiting liver damage. Furthermore, D5 was found to act by modulating the cAMP/PKA/CREB signaling pathway. These findings suggest that the dual PDE3/4 inhibitor D5 is a promising therapeutic candidate for liver injury.
{"title":"Design, synthesis and pharmacological evaluation of dual PDE3/4 inhibitors for therapy of liver injuries","authors":"Gang Li , Xudong Qian , Yan Geng , Jun Wang , Jiaxin Chen , Yanghui Ou , Cheng Chen , Yuchuan Zhong , Wei Pan , Nan Hao , Jiaxin Huang , Guoqin Wu , Qi Zhou , Yali Zhang , Liyan Song , Shuirong Chen , Lianbao Ye , Wen-Hua Chen , Hongliang Yao","doi":"10.1016/j.ejmech.2026.118557","DOIUrl":"10.1016/j.ejmech.2026.118557","url":null,"abstract":"<div><div>Liver injury represents a serious and potentially life-threatening medical condition. Currently, there are no sufficiently targeted or highly effective therapeutic interventions available. Herein, a new series of dual PDE3/4 inhibitors was designed and synthesized for the treatment of liver injury. Among them, compound <strong>D5</strong> exhibited IC<sub>50</sub> values of 10 and 9.4 nM against PDE3A and PDE4B, respectively, and inhibited the pro-inflammatory factor IL-6 (IC<sub>50</sub> = 14.89 μM). In both cholestatic and sepsis–induced liver disease mice models, <strong>D5</strong> significantly reduced the expression levels of inflammatory markers in liver tissue and attenuated fibrosis, thereby limiting liver damage. Furthermore, <strong>D5</strong> was found to act by modulating the cAMP/PKA/CREB signaling pathway. These findings suggest that the dual PDE3/4 inhibitor <strong>D5</strong> is a promising therapeutic candidate for liver injury.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118557"},"PeriodicalIF":5.9,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956882","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 : 2026-01-08DOI: 10.1016/j.ejmech.2026.118567
Rong Hu , Xia-Tong Hu , Ying-Yue Yang , Ling-Feng Du , Xiong-Xiong Lan , Peng Luo , Cai-Hua Li , Luo-Ting Yu , Ning-Yu Wang
BCL6 is regarded as a promising therapeutic target for diffuse large B-cell lymphoma. However, most of the current BCL6 inhibitors and degraders have demonstrated limited antitumor efficacy when used as monotherapy. We hypothesized that developing multitarget degraders capable of simultaneously degrading multiple lymphoma-driving proteins might yield superior anti lymphoma activity. In this study, based on the BCL6 inhibitor BI3812, we designed and identified a dual-target degrader A5, which effectively degraded both BCL6 and GSPT1. A5 induced the degradation of BCL6 and GSPT1 in a time- and concentration-dependent manner, restored the expression of BCL6-regulated genes, and significantly promoted DNA damage in Farage cells. Consequently, A5 exhibited enhanced antiproliferative activity compared to the BCL6 inhibitor BI3812 and the BCL6 degrader BI3802, along with induction of cell cycle arrest and apoptosis. Furthermore, A5 significantly downregulated BCL6 and GSPT1 protein levels in vivo. Thus, this study provides a solid foundation for the development of novel multitarget BCL6 degraders with improved anti-lymphoma potential.
{"title":"Design synthesis and biological evaluation of novel BCL6/GSPT1 degrader as anti-DLBCL agent","authors":"Rong Hu , Xia-Tong Hu , Ying-Yue Yang , Ling-Feng Du , Xiong-Xiong Lan , Peng Luo , Cai-Hua Li , Luo-Ting Yu , Ning-Yu Wang","doi":"10.1016/j.ejmech.2026.118567","DOIUrl":"10.1016/j.ejmech.2026.118567","url":null,"abstract":"<div><div>BCL6 is regarded as a promising therapeutic target for diffuse large B-cell lymphoma. However, most of the current BCL6 inhibitors and degraders have demonstrated limited antitumor efficacy when used as monotherapy. We hypothesized that developing multitarget degraders capable of simultaneously degrading multiple lymphoma-driving proteins might yield superior anti lymphoma activity. In this study, based on the BCL6 inhibitor <strong>BI3812</strong>, we designed and identified a dual-target degrader <strong>A5</strong>, which effectively degraded both BCL6 and GSPT1. <strong>A5</strong> induced the degradation of BCL6 and GSPT1 in a time- and concentration-dependent manner, restored the expression of BCL6-regulated genes, and significantly promoted DNA damage in Farage cells. Consequently, <strong>A5</strong> exhibited enhanced antiproliferative activity compared to the BCL6 inhibitor <strong>BI3812</strong> and the BCL6 degrader <strong>BI3802</strong>, along with induction of cell cycle arrest and apoptosis. Furthermore, <strong>A5</strong> significantly downregulated BCL6 and GSPT1 protein levels in vivo. Thus, this study provides a solid foundation for the development of novel multitarget BCL6 degraders with improved anti-lymphoma potential.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118567"},"PeriodicalIF":5.9,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145947736","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 : 2026-01-08DOI: 10.1016/j.ejmech.2026.118568
Cheng-Han Lin , Hua-Hsin Chiang , Xin-Rui Yang , Tzu-Ching Lin , Chin-Hung Tsai , Chih-Sheng Lin
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) initiates viral infection by binding its surface spike protein to the human angiotensin-converting enzyme 2 (hACE2) receptor. Precise delineation of spike–hACE2 engagement is essential for viral entry and a prime target for therapeutic intervention. However, the current antiviral strategies provided only endpoint readouts and delayed the prioritization against emerging variants. Here, this study introduced novel antiviral compounds designed via a NanoLuc Binary Technology-based pseudovirus [NanoBiT; a structural complementation reporter composed of a Large BiT (LgBiT) and a Small BiT (SmBiT)]. Upon Omicron BA.2-SmBiT spike pseudoviruses infecting LgBiT–hACE2 cells, reconstituted NanoLuc generated quantifiable bioluminescence for real-time spike–hACE2 interaction during viral infection. Within this framework, dual-functional theranostic Anti-spike peptide (S7; ACTPHVSPTHCS) and the Anti-hACE2 peptide (A6; WSTDPGAHLRDY) were identified that not only inhibit SARS-CoV-2 entry by targeting spike and hACE2 proteins, but also serve as diagnostic probes for real-time monitoring. Under optimized conditions, significant inhibition of virus infection was validated in both Anti-spike peptide-treated pseudovirus and Anti-hACE2 peptide-treated hACE2 cells, with a synergistic score of 17.092. Cross-variant efficacy extended to the Omicron JN.1 lineage using a newly constructed JN.1-SmBiT pseudovirus, with molecular docking supporting binding at conserved residues. LgBiT–hACE2 transgenic mice and noninvasive bioluminescence imaging verified in vivo suppression and demonstrated enhanced inhibition with combined treatment. This programmable peptide–NanoBiT framework provided multifunctional compounds that integrate therapeutic efficacy with diagnostic capability. Importantly, the modular design highlights its adaptability to other virus–receptor interactions to underscore its potential in pandemic preparedness.
{"title":"Novel dual-functional peptides designed via NanoBiT spike pseudovirus system for real-time monitoring and inhibition of SARS-CoV-2 infection","authors":"Cheng-Han Lin , Hua-Hsin Chiang , Xin-Rui Yang , Tzu-Ching Lin , Chin-Hung Tsai , Chih-Sheng Lin","doi":"10.1016/j.ejmech.2026.118568","DOIUrl":"10.1016/j.ejmech.2026.118568","url":null,"abstract":"<div><div>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) initiates viral infection by binding its surface spike protein to the human angiotensin-converting enzyme 2 (hACE2) receptor. Precise delineation of spike–hACE2 engagement is essential for viral entry and a prime target for therapeutic intervention. However, the current antiviral strategies provided only endpoint readouts and delayed the prioritization against emerging variants. Here, this study introduced novel antiviral compounds designed via a NanoLuc Binary Technology-based pseudovirus [NanoBiT; a structural complementation reporter composed of a Large BiT (LgBiT) and a Small BiT (SmBiT)]. Upon Omicron BA.2-SmBiT spike pseudoviruses infecting LgBiT–hACE2 cells, reconstituted NanoLuc generated quantifiable bioluminescence for real-time spike–hACE2 interaction during viral infection. Within this framework, dual-functional theranostic Anti-spike peptide (S7; ACTPHVSPTHCS) and the Anti-hACE2 peptide (A6; WSTDPGAHLRDY) were identified that not only inhibit SARS-CoV-2 entry by targeting spike and hACE2 proteins, but also serve as diagnostic probes for real-time monitoring. Under optimized conditions, significant inhibition of virus infection was validated in both Anti-spike peptide-treated pseudovirus and Anti-hACE2 peptide-treated hACE2 cells, with a synergistic score of 17.092. Cross-variant efficacy extended to the Omicron JN.1 lineage using a newly constructed JN.1-SmBiT pseudovirus, with molecular docking supporting binding at conserved residues. LgBiT–hACE2 transgenic mice and noninvasive bioluminescence imaging verified <em>in vivo</em> suppression and demonstrated enhanced inhibition with combined treatment. This programmable peptide–NanoBiT framework provided multifunctional compounds that integrate therapeutic efficacy with diagnostic capability. Importantly, the modular design highlights its adaptability to other virus–receptor interactions to underscore its potential in pandemic preparedness.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118568"},"PeriodicalIF":5.9,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145920574","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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