Prostate-specific membrane antigen (PSMA) is a crucial zinc-containing metalloprotease that belongs to the type II transmembrane protein family, also known as glutamate carboxypeptidase II (GCPII). PSMA stands out as a highly promising target for the diagnosis and treatment of prostate cancer. In this study, we present the design and synthesis of 12 PSMA-targeted DOTA-conjugates, along with comprehensive assessments of their physicochemical properties, in vitro investigations, and in vivo biodistribution evaluations of four leading conjugates. The synthesized conjugates demonstrate remarkable stability in biological fluids. Our findings reveal that the four [68Ga]-radioconjugates exhibit superior or comparable affinity and internalization parameters toward the PSMA-expressing LNCaP cell line in comparison to the conjugate [68Ga]Ga-PSMA-617. Notably, we observed no significant cytotoxicity in any of the [68Ga]-labeled conjugates. Furthermore, these labeled conjugates consistently show high affinity and internalization values with the LNCaP cell line in vitro. Importantly, the conjugate [68Ga]Ga-13.1c demonstrates a good accumulation in the tumor tissues, and achieves the most optimal kidney-to-tumor accumulation ratio in vivo, surpassing the performance of the FDA-approved conjugate [68Ga]Ga-PSMA-11. This establishes [68Ga]Ga-13.1c as a leading candidate in the pursuit of effective prostate cancer treatment.
{"title":"A series of conjugates based on prostate-specific membrane antigen ligands with the chelating agent DOTA: synthesis, radiolabeling, and biological activity.","authors":"N.S. Butakova, A.A. Uspenskaia, N.Y. Zyk, S.A. Petrov, K.A. Popovicheva, A.S. Lunev, K.A. Petrosova, I.A. Mitrofanov, M.N. Ivashkovskaya, S.A. Evteev, Y.A. Ivanenkov, E.K. Beloglazkina, A.A. Larenkov, A.E. Machulkin","doi":"10.1016/j.ejmech.2025.118433","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118433","url":null,"abstract":"Prostate-specific membrane antigen (PSMA) is a crucial zinc-containing metalloprotease that belongs to the type II transmembrane protein family, also known as glutamate carboxypeptidase II (GCPII). PSMA stands out as a highly promising target for the diagnosis and treatment of prostate cancer. In this study, we present the design and synthesis of 12 PSMA-targeted DOTA-conjugates, along with comprehensive assessments of their physicochemical properties, <em>in vitro</em> investigations, and <em>in vivo</em> biodistribution evaluations of four leading conjugates. The synthesized conjugates demonstrate remarkable stability in biological fluids. Our findings reveal that the four [<sup>68</sup>Ga]-radioconjugates exhibit superior or comparable affinity and internalization parameters toward the PSMA-expressing LNCaP cell line in comparison to the conjugate [<sup>68</sup>Ga]Ga-<strong>PSMA-617</strong>. Notably, we observed no significant cytotoxicity in any of the [<sup>68</sup>Ga]-labeled conjugates. Furthermore, these labeled conjugates consistently show high affinity and internalization values with the LNCaP cell line <em>in vitro</em>. Importantly, the conjugate [<sup>68</sup>Ga]Ga-<strong>13.1c</strong> demonstrates a good accumulation in the tumor tissues, and achieves the most optimal kidney-to-tumor accumulation ratio <em>in vivo</em>, surpassing the performance of the FDA-approved conjugate [68Ga]Ga-<strong>PSMA-11</strong>. This establishes [<sup>68</sup>Ga]Ga-<strong>13.1c</strong> as a leading candidate in the pursuit of effective prostate cancer treatment.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"1 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145665186","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 : 2025-12-04DOI: 10.1016/j.ejmech.2025.118456
Zhongkai Zou , Tangyang Ji , Yanting Zhang, Jianfan Cai, Yukang Lin, Bei Zhang, Peiliang Zhao
On the basis of our previous work, a novel series of CA-4 derivatives as tubulin/HDAC6 dual-target inhibitors were discovered by merging hydroxamic acid or benzamide group into the olefin moiety. Among them, compound 9q exhibited satisfactory antiproliferative effects on both hematological malignancies and solid tumor cells with IC50 values ranging from 0.52 to 5.10 μM. The mechanism study revealed that 9q not only repressed tubulin polymerization, disrupted cellular microtubule networks but also inhibited HDAC6. Meanwhile, 9q could induce G2/M phase arrest, and caused cell apoptosis with a concentration-dependent manner, and also remarkably inhibited migration in HeLa cells. Most importantly, 9q effectively inhibited tumor growth in the HCT116 xenograft model without apparent toxicity. These findings indicate that 9q could be a potential lead compound for further development as an antitumor agent.
{"title":"Design, synthesis and bioevaluation of novel combretastatin A-4 based derivatives as potent tubulin/HDAC6 dual-target inhibitors for cancer therapy","authors":"Zhongkai Zou , Tangyang Ji , Yanting Zhang, Jianfan Cai, Yukang Lin, Bei Zhang, Peiliang Zhao","doi":"10.1016/j.ejmech.2025.118456","DOIUrl":"10.1016/j.ejmech.2025.118456","url":null,"abstract":"<div><div>On the basis of our previous work, a novel series of CA-4 derivatives as tubulin/HDAC6 dual-target inhibitors were discovered by merging hydroxamic acid or benzamide group into the olefin moiety. Among them, compound <strong>9q</strong> exhibited satisfactory antiproliferative effects on both hematological malignancies and solid tumor cells with IC<sub>50</sub> values ranging from 0.52 to 5.10 μM. The mechanism study revealed that <strong>9q</strong> not only repressed tubulin polymerization, disrupted cellular microtubule networks but also inhibited HDAC6. Meanwhile, <strong>9q</strong> could induce G<sub>2</sub>/M phase arrest, and caused cell apoptosis with a concentration-dependent manner, and also remarkably inhibited migration in HeLa cells. Most importantly, <strong>9q</strong> effectively inhibited tumor growth in the HCT116 xenograft model without apparent toxicity. These findings indicate that <strong>9q</strong> could be a potential lead compound for further development as an antitumor agent.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118456"},"PeriodicalIF":5.9,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145665185","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}
Farnesoid X receptor (FXR), a nuclear receptor, plays an important role in regulating metabolic dysfunction-associated steatohepatitis (MASH). However, clinical studies have demonstrated severe side effects in patients treated with FXR full agonists, underscoring the need for partial agonists that can modulate FXR activity in a more controlled manner. Such partial agonists could provide effective MASH treatment while minimizing adverse effects. Herein, we report compound V15, a potent and selective FXR partial agonist featuring a 1-(4-aminophenylacetyl)piperidine scaffold. V15 demonstrates an EC50 value of 0.67 ± 0.08 nM (81.3% maximum efficacy vs obeticholic acid). Additionally, V15 dose-dependently reduces steatosis and lowers TG levels in HepG2 cells. Significantly, V15 ameliorates high-fat and high-sugar diet-induced MASH in mice by mitigating hepatic steatosis, inflammation, and fibrosis. It also protects against α-naphthyl isothiocyanate-induced liver injury. Notably, V15 exhibits good target selectivity and an acceptable safety profile. These findings suggest that the novel FXR partial agonist V15 represents a promising candidate for the treatment of MASH.
{"title":"Discovery of novel 1-(4-aminophenylacetyl)piperidine derivatives as FXR partial agonists for the potential treatment of metabolic dysfunction-associated steatohepatitis","authors":"Bing Zhang, Jiaojiao Tu, Zhenghu Ban, Yanfen Peng, Yihuan Zhou, Qiming Yu, Xiangduan Tan","doi":"10.1016/j.ejmech.2025.118460","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118460","url":null,"abstract":"Farnesoid X receptor (FXR), a nuclear receptor, plays an important role in regulating metabolic dysfunction-associated steatohepatitis (MASH). However, clinical studies have demonstrated severe side effects in patients treated with FXR full agonists, underscoring the need for partial agonists that can modulate FXR activity in a more controlled manner. Such partial agonists could provide effective MASH treatment while minimizing adverse effects. Herein, we report compound <strong>V15</strong>, a potent and selective FXR partial agonist featuring a 1-(4-aminophenylacetyl)piperidine scaffold. <strong>V15</strong> demonstrates an EC<sub>50</sub> value of 0.67 ± 0.08 nM (81.3% maximum efficacy <em>vs</em> obeticholic acid). Additionally, <strong>V15</strong> dose-dependently reduces steatosis and lowers TG levels in HepG2 cells. Significantly, <strong>V15</strong> ameliorates high-fat and high-sugar diet-induced MASH in mice by mitigating hepatic steatosis, inflammation, and fibrosis. It also protects against α-naphthyl isothiocyanate-induced liver injury. Notably, <strong>V15</strong> exhibits good target selectivity and an acceptable safety profile. These findings suggest that the novel FXR partial agonist <strong>V15</strong> represents a promising candidate for the treatment of MASH.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"21 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145665183","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 : 2025-12-04DOI: 10.1016/j.ejmech.2025.118465
Yanchen Li, Jin Wang, Junyu Zhang, Tingting Liu, Yuanyuan Shan, Jie Zhang
The development of drug resistance in tumors attributed to vascular abnormality hinders anti-angiogenic treatments. While vascular normalization strategy offer promise, the absence of clearly defined targets and drugs remains a notable challenge. In a prior study, our research team pinpointed QDAU5, a quinazolinone active compound with vascular-normalizing properties, which was found to selectively bind to and inhibit the phosphorylation of EphrinB2, thereby EphrinB2 emerges as a promising therapeutic target for drug development. Herein, we constructed two types of multifunctional photoaffinity probes based on QDAU5 by in situ assembly of diazirine photosensitizing motifs and bio-orthogonal functional motif, demonstrating concurrent antitumor and vascular normalization activities. Through the incorporation of bioorthogonal labeling/purification motifs, we have achieved the labeling, purification and identification of the target protein EphrinB2, and analyzed its binding site, thus elucidating EphrinB2 as a drug target for tumor vascular normalization therapeutic strategy.
{"title":"Discovery of Drug Target for Vascular Normalization through Multifunctional photoaffinity probes","authors":"Yanchen Li, Jin Wang, Junyu Zhang, Tingting Liu, Yuanyuan Shan, Jie Zhang","doi":"10.1016/j.ejmech.2025.118465","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118465","url":null,"abstract":"The development of drug resistance in tumors attributed to vascular abnormality hinders anti-angiogenic treatments. While vascular normalization strategy offer promise, the absence of clearly defined targets and drugs remains a notable challenge. In a prior study, our research team pinpointed <strong>QDAU5</strong>, a quinazolinone active compound with vascular-normalizing properties, which was found to selectively bind to and inhibit the phosphorylation of EphrinB2, thereby EphrinB2 emerges as a promising therapeutic target for drug development. Herein, we constructed two types of multifunctional photoaffinity probes based on <strong>QDAU5</strong> by in situ assembly of diazirine photosensitizing motifs and bio-orthogonal functional motif, demonstrating concurrent antitumor and vascular normalization activities. Through the incorporation of bioorthogonal labeling/purification motifs, we have achieved the labeling, purification and identification of the target protein EphrinB2, and analyzed its binding site, thus elucidating EphrinB2 as a drug target for tumor vascular normalization therapeutic strategy.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"5 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145674046","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 : 2025-12-04DOI: 10.1016/j.ejmech.2025.118437
Yichun Shi, Heng Zhang, Shiqin Cong, Xingyu Zhu, Yao Liu, Jinjin Li, Ke Tang, Rong Xue, Xiuxiu Liu, Zhenghuai Tan, Junli Chen, Yong Deng
Based on multitarget-directed-ligands (MTDLs) strategy, a series of benzylpiperidine-pyridazin-3(2H)-ones were designed, synthesized and evaluated as innovative multifunctional agents for Alzheimer’s disease (AD). Biological evaluation revealed that most compounds exhibited excellent acetylcholinesterase (AChE) inhibition, potent antioxidant activity and moderate β-amyloid (Aβ1-42) aggregation inhibition. Among them, compound 7a emerged as a synergistic multifunctional agent with significant inhibition of AChE (EeAChE: IC50 = 0.21 μM; HsAChE: IC50 = 13 nM) and anti-Aβ activity (IC50 = 2.92 μM for self-induced Aβ1-42 aggregation; IC50 = 1.28 μM for disaggregation of Aβ1-42 fibrils; IC50 = 3.72 μM for Cu2+-induced Aβ1-42 aggregation; IC50 = 2.16 μM for disaggregation of Cu2+-induced Aβ1-42 fibrils). In addition, 7a was endowed with the potential to serve as antioxidant (2.88 Trolox equivalents), metals chelator and anti-neuroinflammatory agent for synergistic treatment. Moreover, 7a exhibited pronounced neuroprotective effects across multiple cellular models. Pharmacokinetically, 7a displayed favorable brain penetration (AUCbrain/plasma = 0.77) and sustained exposure. In vivo evaluation demonstrated that 7a effectively ameliorated scopolamine-induced cognitive impairment in the Morris water maze, which was associated with restored cholinergic function and mitigated oxidative stress in mice. The synergistic multi-target efficacy combined with favorable pharmacokinetic properties underscores its potential as a disease-modifying therapeutic agent for AD.
{"title":"Benzylpiperidine-pyridazin-3(2H)-one derivatives as potential multifunctional agents against Alzheimer's disease","authors":"Yichun Shi, Heng Zhang, Shiqin Cong, Xingyu Zhu, Yao Liu, Jinjin Li, Ke Tang, Rong Xue, Xiuxiu Liu, Zhenghuai Tan, Junli Chen, Yong Deng","doi":"10.1016/j.ejmech.2025.118437","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118437","url":null,"abstract":"Based on multitarget-directed-ligands (MTDLs) strategy, a series of benzylpiperidine-pyridazin-3(<em>2H</em>)-ones were designed, synthesized and evaluated as innovative multifunctional agents for Alzheimer’s disease (AD). Biological evaluation revealed that most compounds exhibited excellent acetylcholinesterase (AChE) inhibition, potent antioxidant activity and moderate <em>β</em>-amyloid (A<em>β</em><sub>1-42</sub>) aggregation inhibition. Among them, compound <strong>7a</strong> emerged as a synergistic multifunctional agent with significant inhibition of AChE (<em>Ee</em>AChE: IC<sub>50</sub> = 0.21 μM; <em>Hs</em>AChE: IC<sub>50</sub> = 13 nM) and anti-A<em>β</em> activity (IC<sub>50</sub> = 2.92 μM for self-induced A<em>β</em><sub>1-42</sub> aggregation; IC<sub>50</sub> = 1.28 μM for disaggregation of A<em>β</em><sub>1-42</sub> fibrils; IC<sub>50</sub> = 3.72 μM for Cu<sup>2+</sup>-induced A<em>β</em><sub>1-42</sub> aggregation; IC<sub>50</sub> = 2.16 μM for disaggregation of Cu<sup>2+</sup>-induced A<em>β</em><sub>1-42</sub> fibrils). In addition, <strong>7a</strong> was endowed with the potential to serve as antioxidant (2.88 Trolox equivalents), metals chelator and anti-neuroinflammatory agent for synergistic treatment. Moreover, <strong>7a</strong> exhibited pronounced neuroprotective effects across multiple cellular models. Pharmacokinetically, <strong>7a</strong> displayed favorable brain penetration (AUC<sub>brain/plasma</sub> = 0.77) and sustained exposure. <em>In vivo</em> evaluation demonstrated that <strong>7a</strong> effectively ameliorated scopolamine-induced cognitive impairment in the Morris water maze, which was associated with restored cholinergic function and mitigated oxidative stress in mice. The synergistic multi-target efficacy combined with favorable pharmacokinetic properties underscores its potential as a disease-modifying therapeutic agent for AD.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"12 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145665242","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}
Melanoma, a highly metastatic cancer with rising incidence, faces therapeutic challenges due to drug resistance and recurrence. In this study, we designed novel 1,2,3-triazole-benzoxazinone hybrids via pharmacophore hybridization to address these limitations. Lead compounds 3e and 4d demonstrated potent anti-melanoma activity, with IC50 values of 5.26 μM (3e) and 9.42 μM (4d) in A375 cells, and 8.9 μM (3e) and 3.63 μM (4d) in SK28 cells, respectively. Mechanistically, they induced ferroptosis, a first-in-class mechanism for this scaffold, by downregulating SLC7A11, and GPX4, triggering ROS accumulation and lipid peroxidation—effects reversed by ferroptosis inhibitor Fer-1. Molecular docking confirmed direct binding to GPX4’s active site via π-π stacking and hydrogen bonds, promoting its proteasomal degradation. Structural optimization enhanced selectivity: derivatives showed negligible toxicity in normal cells and murine models, achieving a 3-5-fold higher therapeutic index than conventional agents. This study pioneers a dual-functional scaffold hybridization strategy, merging synthetic innovation with ferroptosis induction to overcome resistance. The robust efficacy, mechanistic clarity, and superior safety profile of 3e and 4d position them as transformative candidates for metastatic melanoma therapy, offering a novel approach to combat drug resistance and toxicity barriers.
{"title":"Chemical induction of ferroptosis through GPX4 inhibition: Rational Design of Triazole-Benzoxazine Hybrids for melanoma therapy","authors":"Bingbing Feng, Yuxin Chen, Haizhou Fu, Yufei Li, Jingjing Guo, Xixi Hou, Huibin Xu, Shuxiang Xu","doi":"10.1016/j.ejmech.2025.118434","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118434","url":null,"abstract":"Melanoma, a highly metastatic cancer with rising incidence, faces therapeutic challenges due to drug resistance and recurrence. In this study, we designed novel 1,2,3-triazole-benzoxazinone hybrids via pharmacophore hybridization to address these limitations. Lead compounds <strong>3e</strong> and <strong>4d</strong> demonstrated potent anti-melanoma activity, with IC50 values of 5.26 μM (<strong>3e</strong>) and 9.42 μM (<strong>4d</strong>) in A375 cells, and 8.9 μM (<strong>3e</strong>) and 3.63 μM (<strong>4d</strong>) in SK28 cells, respectively. Mechanistically, they induced ferroptosis, a first-in-class mechanism for this scaffold, by downregulating SLC7A11, and GPX4, triggering ROS accumulation and lipid peroxidation—effects reversed by ferroptosis inhibitor <em>Fer-1</em>. Molecular docking confirmed direct binding to GPX4’s active site via π-π stacking and hydrogen bonds, promoting its proteasomal degradation. Structural optimization enhanced selectivity: derivatives showed negligible toxicity in normal cells and murine models, achieving a 3-5-fold higher therapeutic index than conventional agents. This study pioneers a dual-functional scaffold hybridization strategy, merging synthetic innovation with ferroptosis induction to overcome resistance. The robust efficacy, mechanistic clarity, and superior safety profile of <strong>3e</strong> and <strong>4d</strong> position them as transformative candidates for metastatic melanoma therapy, offering a novel approach to combat drug resistance and toxicity barriers.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"51 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145665184","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 : 2025-12-03DOI: 10.1016/j.ejmech.2025.118446
Jinjin Lai, Chengpeng Tao, Feng Jiang, Deping Li
Disruptor of telomeric silencing 1-like (DOT1L) is a histone lysine methyltransferase (HMT) that uses S-adenosyl-L-methionine (SAM) as a methyl donor to catalyze the mono-, di-, and tri-methylation of histone H3 lysine 79 (H3K79) within nucleosomes, generating S-adenosyl-L-homocysteine (SAH) as the enzymatic byproduct. Aberrant DOT1L activity drives the overexpression of oncogenes and the development of mixed lineage leukemia (MLL). Consequently, targeted inhibition of the catalytic domain of DOT1L or disruption of its interaction with MLL fusion proteins is a promising therapeutic strategy for MLL. This review comprehensively summarizes the structure and biological functions of DOT1L, focusing on the research progress of small-molecule modulators, including nucleoside/non-nucleoside inhibitors, protein–protein interaction (PPI) disruptors, dual-target inhibitors, and proteolysis-targeting chimera (PROTAC) molecules, from the perspective of drug design. In addition, this review discusses challenges and future perspectives associated with the discovery of DOT1L-targeted therapies for cancer.
{"title":"A medicinal chemistry perspective on disruptor of telomeric silencing 1-like: Its mechanisms and modulators in cancer treatment","authors":"Jinjin Lai, Chengpeng Tao, Feng Jiang, Deping Li","doi":"10.1016/j.ejmech.2025.118446","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118446","url":null,"abstract":"Disruptor of telomeric silencing 1-like (DOT1L) is a histone lysine methyltransferase (HMT) that uses S-adenosyl-L-methionine (SAM) as a methyl donor to catalyze the mono-, di-, and tri-methylation of histone H3 lysine 79 (H3K79) within nucleosomes, generating S-adenosyl-L-homocysteine (SAH) as the enzymatic byproduct. Aberrant DOT1L activity drives the overexpression of oncogenes and the development of mixed lineage leukemia (MLL). Consequently, targeted inhibition of the catalytic domain of DOT1L or disruption of its interaction with MLL fusion proteins is a promising therapeutic strategy for MLL. This review comprehensively summarizes the structure and biological functions of DOT1L, focusing on the research progress of small-molecule modulators, including nucleoside/non-nucleoside inhibitors, protein–protein interaction (PPI) disruptors, dual-target inhibitors, and proteolysis-targeting chimera (PROTAC) molecules, from the perspective of drug design. In addition, this review discusses challenges and future perspectives associated with the discovery of DOT1L-targeted therapies for cancer.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"202 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145674047","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 : 2025-12-03DOI: 10.1016/j.ejmech.2025.118411
Meenu , Khursheed Ahmad Sheikh , M. Shaquiquzzaman , Shivam Gupta , Barkha , Sharba Tasneem , Mymoona Akhter , Tariq Anwer , Mohammad Kaleem , Suruchi Singh , M. Mumtaz Alam
The epidermal growth factor receptor (EGFR) stands as a cornerstone therapeutic target in oncology, particularly non-small cell lung cancer (NSCLC), where it drives tumor proliferation amid a saturated field of inhibitors and analyses. This review offers a targeted exploration of the core pharmacophoric traits shaping EGFR inhibitor potency through evolving generations, aiming to guide the creation of advanced agents that sidestep resistance. Drawing from an extensive survey of published pharmacophore frameworks and crystallographic data on approved inhibitors, we spotlight persistent binding motifs and their impact on potency and specificity. Using gefitinib as a foundational scaffold and aligning it with the EGFR structure (PDB: 4WKQ), we map essential engagements-such as hinge-directed hydrogen bonds often via quinazoline cores, hydrophobic nesting in the ATP pocket, and pi-stacking for anchor stability-while tracing refinements like covalent warheads and flexible solvent tails that bolster mutant selectivity. Unlike conventional summaries, our approach fuses structure-activity insights from docking simulations (refined through molecular dynamics) with validated lab assays, focusing on high-confidence candidates boasting sub-nanomolar activity and clean kinase profiles to filter out artifacts. Across more than 50 quinazoline-based and alternative scaffolds, we uncover universal binding drivers alongside tailored tweaks, including triazole add-ons that boost affinity for T790 M and C797S variants by two-fold to five-fold, curbing off-target effects. These patterns expose hidden trends in evasion of polypharmacology and lay groundwork for a versatile pharmacophore template suited to novel scaffold invention. Ultimately, this blended computational-experimental lens equips medicinal chemists with tools to accelerate lead optimization, crafting durable third- and fourth-generation options that adapt to shifting resistance landscapes and elevate EGFR-directed treatments.
{"title":"Pharmacophore-guided review of EGFR-targeted anticancer drugs with gefitinib as a reference","authors":"Meenu , Khursheed Ahmad Sheikh , M. Shaquiquzzaman , Shivam Gupta , Barkha , Sharba Tasneem , Mymoona Akhter , Tariq Anwer , Mohammad Kaleem , Suruchi Singh , M. Mumtaz Alam","doi":"10.1016/j.ejmech.2025.118411","DOIUrl":"10.1016/j.ejmech.2025.118411","url":null,"abstract":"<div><div>The epidermal growth factor receptor (EGFR) stands as a cornerstone therapeutic target in oncology, particularly non-small cell lung cancer (NSCLC), where it drives tumor proliferation amid a saturated field of inhibitors and analyses. This review offers a targeted exploration of the core pharmacophoric traits shaping EGFR inhibitor potency through evolving generations, aiming to guide the creation of advanced agents that sidestep resistance. Drawing from an extensive survey of published pharmacophore frameworks and crystallographic data on approved inhibitors, we spotlight persistent binding motifs and their impact on potency and specificity. Using gefitinib as a foundational scaffold and aligning it with the EGFR structure (PDB: 4WKQ), we map essential engagements-such as hinge-directed hydrogen bonds often via quinazoline cores, hydrophobic nesting in the ATP pocket, and pi-stacking for anchor stability-while tracing refinements like covalent warheads and flexible solvent tails that bolster mutant selectivity. Unlike conventional summaries, our approach fuses structure-activity insights from docking simulations (refined through molecular dynamics) with validated lab assays, focusing on high-confidence candidates boasting sub-nanomolar activity and clean kinase profiles to filter out artifacts. Across more than 50 quinazoline-based and alternative scaffolds, we uncover universal binding drivers alongside tailored tweaks, including triazole add-ons that boost affinity for T790 M and C797S variants by two-fold to five-fold, curbing off-target effects. These patterns expose hidden trends in evasion of polypharmacology and lay groundwork for a versatile pharmacophore template suited to novel scaffold invention. Ultimately, this blended computational-experimental lens equips medicinal chemists with tools to accelerate lead optimization, crafting durable third- and fourth-generation options that adapt to shifting resistance landscapes and elevate EGFR-directed treatments.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118411"},"PeriodicalIF":5.9,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145665187","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 : 2025-12-03DOI: 10.1016/j.ejmech.2025.118461
Anna Kozakiewicz-Piekarz, Oleg M. Demchuk, Magdalena Grzegórska, Maja Mielcarz, Antonina Kurowska-Okoń, Karolina Herda, Małgorzata Sadczuk, Lanka Suneel, Piotr Szczepański, Anna Ciarkowska, Magdalena Wujak
Adenylate kinases (AKs) are a family of highly conserved enzymes that catalyze the reversible phosphotransfer between two ADP molecules to generate ATP and AMP, thereby maintaining nucleotide homeostasis and supporting cellular energy dynamics. Among the nine human isoenzymes, AK1 is one of the most extensively studied and is implicated in both neurodegeneration and inflammation. Elevated AK1 activity has been associated with tau pathology and retinal inflammation, suggesting that its inhibition may help restore nucleotide homeostasis and alleviate these pathological conditions. In pursuit of potent AK1 modulators, we investigated derivatives of phenylcyanomethylenequinone oxime (4-AN), a scaffold previously reported as an ATP-competitive inhibitor of protein kinases. A library of 25 compounds was examined: 9 with synthesis previously reported and 16 newly synthesized by introducing substituents on the phenyl and methylenequinone rings and by O-functionalizing the oxime group with various alkyl and acyl chains. Several phenylcyanomethylenequinone oxime derivatives exhibited moderate to strong inhibition of human AK1 (hAK1), with the most active compounds demonstrating IC50 values around 15 μM. Structure–activity analysis revealed that hydrophobic, bulky groups at the oxime position enhance inhibition, likely through allosteric interactions. The tested compounds were found to act via a non-competitive mechanism, binding near the LID domain, which plays a key role in the catalytic process. Chemometric and QSAR analyses indicated that the most active compounds share common physicochemical features, supporting the potential of 4-AN derivatives as a novel scaffold for potent, non-competitive AK1 inhibitors.
{"title":"Targeting human adenylate kinase 1 (hAK1) with phenylcyanomethylenequinone oximes: a novel scaffold of non-competitive inhibitors – synthesis, kinetic studies, SAR and QSAR analysis","authors":"Anna Kozakiewicz-Piekarz, Oleg M. Demchuk, Magdalena Grzegórska, Maja Mielcarz, Antonina Kurowska-Okoń, Karolina Herda, Małgorzata Sadczuk, Lanka Suneel, Piotr Szczepański, Anna Ciarkowska, Magdalena Wujak","doi":"10.1016/j.ejmech.2025.118461","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118461","url":null,"abstract":"Adenylate kinases (AKs) are a family of highly conserved enzymes that catalyze the reversible phosphotransfer between two ADP molecules to generate ATP and AMP, thereby maintaining nucleotide homeostasis and supporting cellular energy dynamics. Among the nine human isoenzymes, AK1 is one of the most extensively studied and is implicated in both neurodegeneration and inflammation. Elevated AK1 activity has been associated with tau pathology and retinal inflammation, suggesting that its inhibition may help restore nucleotide homeostasis and alleviate these pathological conditions. In pursuit of potent AK1 modulators, we investigated derivatives of phenylcyanomethylenequinone oxime (4-AN), a scaffold previously reported as an ATP-competitive inhibitor of protein kinases. A library of 25 compounds was examined: 9 with synthesis previously reported and 16 newly synthesized by introducing substituents on the phenyl and methylenequinone rings and by <em>O</em>-functionalizing the oxime group with various alkyl and acyl chains. Several phenylcyanomethylenequinone oxime derivatives exhibited moderate to strong inhibition of human AK1 (hAK1), with the most active compounds demonstrating IC<sub>50</sub> values around 15 μM. Structure–activity analysis revealed that hydrophobic, bulky groups at the oxime position enhance inhibition, likely through allosteric interactions. The tested compounds were found to act <em>via</em> a non-competitive mechanism, binding near the LID domain, which plays a key role in the catalytic process. Chemometric and QSAR analyses indicated that the most active compounds share common physicochemical features, supporting the potential of 4-AN derivatives as a novel scaffold for potent, non-competitive AK1 inhibitors.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"129 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145665231","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 : 2025-12-03DOI: 10.1016/j.ejmech.2025.118445
Annalida Bedini, Francesca Galvani, Gian Marco Elisi, Laura Scalvini, Michele Mari, Adriano Recchia, Pedro Augusto C.M. Fernandes, Gabriela S. Kinker, Valeria Lucini, Francesco Scaglione, Fabrizio Vincenzi, Katia Varani, Regina P. Markus, Silvia Rivara, Gilberto Spadoni, Marco Mor
{"title":"N-Acylaminoethyltetrahydroquinolines: a new class of melatonin receptor ligands with in vivo activity on glioblastoma","authors":"Annalida Bedini, Francesca Galvani, Gian Marco Elisi, Laura Scalvini, Michele Mari, Adriano Recchia, Pedro Augusto C.M. Fernandes, Gabriela S. Kinker, Valeria Lucini, Francesco Scaglione, Fabrizio Vincenzi, Katia Varani, Regina P. Markus, Silvia Rivara, Gilberto Spadoni, Marco Mor","doi":"10.1016/j.ejmech.2025.118445","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.118445","url":null,"abstract":"","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"27 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657637","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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