Microtubule targeting agents are effective in cancer therapy, but current inhibitors face challenges including systemic toxicity and P-glycoprotein (P-gp) mediated drug resistance, underscoring the need for novel microtubule inhibitors. Quinazolin-4(3H)-one alkaloids, with diverse targets, exhibit significant potential for developing novel anti-cancer agents. Herein, inspired by marine quinazolin-4(3H)-one alkaloid penipanoid C, compounds 1‒55, a series of 2-(3,4,5-trimethoxybenzoyl)quinazolin-4(3H)-one derivatives were synthesized and identified. Among them, CHNQD-01522 (18) exhibited the strongest cytotoxic activity against Huh-7 and HepG2 cell lines with IC50 values of 0.19 and 0.17 μM. Meanwhile, treatment with CHNQD-01522 (18) suppressed tumor cell colony formation, arrested cell cycle in G2/M phases, and induced apoptosis. Mechanistic studies revealed that it is a novel microtubule inhibitor targeting the colchicine binding site, which cannot be transported by P-gp in cancer cells. Encouragingly, CHNQD-01522 (18) showed significant in vivo anti-tumor efficacy in the subcutaneous xenograft tumor model (TID, TGI = 79.09%) with frequency dependence. More importantly, the anti-tumor efficacy was also verified in an orthotopic xenograft tumor model. Furthermore, CHNQD-01522 (18) displayed satisfactory safety profiles in preliminary toxicity studies. Taken together, this study has identified a novel microtubule inhibitor with significant anti-hepatocellular carcinoma (HCC) activity, inherent resistance-avoidance property, and a favorable safety profile, showing promise as an HCC therapeutic.
{"title":"Marine natural product-inspired 2-(3,4,5-trimethoxybenzoyl)quinazolin-4(3H)-one derivative CHNQD-01522: a novel anti-hepatocellular carcinoma agent targeting colchicine binding site of microtubule","authors":"Peng-Jie Li, Chao-Jie Wang, Rui-Qin Zhai, Ji-Xiu Gao, Hao-Ran Li, Jian-Yu Liu, Mei-Yan Wei, Yu-Cheng Gu, Chang-Lun Shao","doi":"10.1016/j.ejmech.2026.118658","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118658","url":null,"abstract":"Microtubule targeting agents are effective in cancer therapy, but current inhibitors face challenges including systemic toxicity and P-glycoprotein (P-gp) mediated drug resistance, underscoring the need for novel microtubule inhibitors. Quinazolin-4(3<em>H</em>)-one alkaloids, with diverse targets, exhibit significant potential for developing novel anti-cancer agents. Herein, inspired by marine quinazolin-4(3<em>H</em>)-one alkaloid penipanoid C, compounds <strong>1‒55</strong>, a series of 2-(3,4,5-trimethoxybenzoyl)quinazolin-4(3<em>H</em>)-one derivatives were synthesized and identified. Among them, CHNQD-01522 (<strong>18</strong>) exhibited the strongest cytotoxic activity against Huh-7 and HepG2 cell lines with IC<sub>50</sub> values of 0.19 and 0.17 μM. Meanwhile, treatment with CHNQD-01522 (<strong>18</strong>) suppressed tumor cell colony formation, arrested cell cycle in G2/M phases, and induced apoptosis. Mechanistic studies revealed that it is a novel microtubule inhibitor targeting the colchicine binding site, which cannot be transported by P-gp in cancer cells. Encouragingly, CHNQD-01522 (<strong>18</strong>) showed significant <em>in vivo</em> anti-tumor efficacy in the subcutaneous xenograft tumor model (TID, TGI = 79.09%) with frequency dependence. More importantly, the anti-tumor efficacy was also verified in an orthotopic xenograft tumor model. Furthermore, CHNQD-01522 (<strong>18</strong>) displayed satisfactory safety profiles in preliminary toxicity studies. Taken together, this study has identified a novel microtubule inhibitor with significant anti-hepatocellular carcinoma (HCC) activity, inherent resistance-avoidance property, and a favorable safety profile, showing promise as an HCC therapeutic.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"23 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135330","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 : 2026-02-08DOI: 10.1016/j.ejmech.2026.118647
Hao Jiang, Sandip B. Jadhav, Anil Kumar Soda, Wenjuan Zhou, Hong Chen, Shuxian Xu, Lin Qiu, Tianyu Huang, Zhimin Xing, Lei Zhao, John J. Lee, Ruiqing Ni, Dean F. Wong, Guangyong Peng, Joel S. Perlmutter, Tammie L.S. Benzinger, Zhude Tu
{"title":"Design, synthesis, and characterization of F-18 sigma-1 receptor radiotracers for Alzheimer disease","authors":"Hao Jiang, Sandip B. Jadhav, Anil Kumar Soda, Wenjuan Zhou, Hong Chen, Shuxian Xu, Lin Qiu, Tianyu Huang, Zhimin Xing, Lei Zhao, John J. Lee, Ruiqing Ni, Dean F. Wong, Guangyong Peng, Joel S. Perlmutter, Tammie L.S. Benzinger, Zhude Tu","doi":"10.1016/j.ejmech.2026.118647","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118647","url":null,"abstract":"","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"23 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146138917","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 : 2026-02-07DOI: 10.1016/j.ejmech.2026.118655
Carl P. Soltau, Ban Qi Tay, Alexander P. Martyn, Derek J. Richard, Mark N. Adams, Steven E. Bottle
{"title":"Structure-Activity Relationship of Steroidal-Nitroxide Hybrids: Dual-Modulators of Glucocorticoid Receptor Signalling and Cellular Redox State","authors":"Carl P. Soltau, Ban Qi Tay, Alexander P. Martyn, Derek J. Richard, Mark N. Adams, Steven E. Bottle","doi":"10.1016/j.ejmech.2026.118655","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118655","url":null,"abstract":"","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"72 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146138918","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}
Hyperuricemia is a well-established direct trigger of gouty arthritis. Xanthine oxidase (XO), the rate-limiting enzyme in uric acid production, represents a core therapeutic target for gout. Although XO inhibitors like allopurinol and febuxostat are widely-used clinically, their limitations, including severe hypersensitivity and cardiovascular risks, necessitate the continuous pursuit of safer and more efficient agents. This review provides a systematic and critical assessment of recent advances in XO inhibitor research, proposing for the first time a unified classification framework based on the evolution of drug design strategies. We comprehensively cover diverse chemical entities, from structure-based, rationally designed compounds to natural products and their corresponding analogues, with a particular emphasis on cutting-edge strategies designed to overcome existing drawbacks. These include dual-target inhibitors (e.g., targeting XO/URAT1 or XO/NLRP3) and drug repurposing. By delving into the structure-activity relationships within each inhibitor class, we identify crucial pharmacophores and optimization principles. Finally, the review offers a forward-looking perspective, critically discussing current research challenges and outlining future directions, such as leveraging artificial intelligence and advanced computational simulations for lead optimization. This work is intended to serve as a clear theoretical blueprint and a practical source of inspiration for medicinal chemists designing the next generation of highly effective and low-toxicity anti-gout therapeutics.
{"title":"Xanthine Oxidase Inhibitors for Gout: Applications and Novel Drug Development","authors":"Weiping Lyu, Haoming Qin, Xiaonan Zhou, Yihan Zhang, Dehua Lu, Yongxiang Shao, Yanming Chen, Mingxiu Liang, Qi Li, Xiaowei Chi, Liangren Zhang, Cheng Shi, Zhenming Liu","doi":"10.1016/j.ejmech.2026.118619","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118619","url":null,"abstract":"Hyperuricemia is a well-established direct trigger of gouty arthritis. Xanthine oxidase (XO), the rate-limiting enzyme in uric acid production, represents a core therapeutic target for gout. Although XO inhibitors like allopurinol and febuxostat are widely-used clinically, their limitations, including severe hypersensitivity and cardiovascular risks, necessitate the continuous pursuit of safer and more efficient agents. This review provides a systematic and critical assessment of recent advances in XO inhibitor research, proposing for the first time a unified classification framework based on the evolution of drug design strategies. We comprehensively cover diverse chemical entities, from structure-based, rationally designed compounds to natural products and their corresponding analogues, with a particular emphasis on cutting-edge strategies designed to overcome existing drawbacks. These include dual-target inhibitors (e.g., targeting XO/URAT1 or XO/NLRP3) and drug repurposing. By delving into the structure-activity relationships within each inhibitor class, we identify crucial pharmacophores and optimization principles. Finally, the review offers a forward-looking perspective, critically discussing current research challenges and outlining future directions, such as leveraging artificial intelligence and advanced computational simulations for lead optimization. This work is intended to serve as a clear theoretical blueprint and a practical source of inspiration for medicinal chemists designing the next generation of highly effective and low-toxicity anti-gout therapeutics.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"48 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135339","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}
Infection with the influenza virus provokes an excessive immune reaction, triggering a cytokine storm that can cause severe inflammation and lead to conditions such as pneumonia and myocarditis. Herein, we propose a dual-target strategy that simultaneously targets the viral PB2 protein and the host JAK2 kinase, aiming to not only eliminate the virus but also modulate the immune response, facilitating rapid recovery of the body’s health. In this article, the design and discovery of novel PB2/JAK2 dual-target inhibitors are reported. Through rational design and structure-guided optimization, we identified compound 4B, which exhibited potent anti-H1N1 activity (MDCK cell EC50 = 15 nM) and JAK2 inhibitory activity (JAK2 IC50 = 49 nM). Notably, 4B demonstrated favorable pharmacokinetic properties in mice, achieving excellent oral bioavailability (F = 99.4%). Furthermore, our findings show that compound 4B significantly downregulates NP and PB2 protein expression. Concurrently, 4B also inhibits the mRNA expression of key pro-inflammatory cytokines (IL-6, TNF-α, IFN-β) in both inflammatory and influenza-infected models. This study demonstrates the promising potential of dual inhibition, targeting both viral replication and the host inflammatory response, for the development of anti-influenza therapeutics.
{"title":"Rational Design of Dual PB2/JAK2 Inhibitors Achieving Balanced Antiviral and Host-Directed Immunomodulatory Effects","authors":"Yujian Yang, Binhao Rong, Huanyu Shi, Kunyu Lu, Xinxin Lin, Yuanmei Wen, Xingyu Zhou, Peisen Zheng, Xinshan Deng, Xumu Zhang, Shuwen Liu, Qifan Zhou","doi":"10.1016/j.ejmech.2026.118642","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118642","url":null,"abstract":"Infection with the influenza virus provokes an excessive immune reaction, triggering a cytokine storm that can cause severe inflammation and lead to conditions such as pneumonia and myocarditis. Herein, we propose a dual-target strategy that simultaneously targets the viral PB2 protein and the host JAK2 kinase, aiming to not only eliminate the virus but also modulate the immune response, facilitating rapid recovery of the body’s health. In this article, the design and discovery of novel PB2/JAK2 dual-target inhibitors are reported. Through rational design and structure-guided optimization, we identified compound <strong>4B</strong>, which exhibited potent anti-H1N1 activity (MDCK cell EC<sub>50</sub> = 15 nM) and JAK2 inhibitory activity (JAK2 IC<sub>50</sub> = 49 nM). <strong>Notably, 4B demonstrated favorable pharmacokinetic properties in mice, achieving excellent oral bioavailability (F = 99.4%).</strong> Furthermore, our findings show that compound <strong>4B</strong> significantly downregulates NP and PB2 protein expression. Concurrently, <strong>4B</strong> also inhibits the mRNA expression of key pro-inflammatory cytokines (IL-6, TNF-α, IFN-β) in both inflammatory and influenza-infected models. This study demonstrates the promising potential of dual inhibition, targeting both viral replication and the host inflammatory response, for the development of anti-influenza therapeutics.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"13 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135341","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 : 2026-02-06DOI: 10.1016/j.ejmech.2026.118652
Damian Muszak, Justyna Kocik-Krol, Julia Zaber, Oskar Kruc, Urszula Palej, Karolina Fijolkowska, Agnieszka Maslanka, Katarzyna Magiera-Mularz, Jacek Plewka, Malgorzata Stec, Marcin Surmiak, Malgorzata Szafarz, Maciej Siedlar, Bogdan Musielak, Radoslaw Kitel, Elzbieta Wyska, Lukasz Skalniak, Ewa Surmiak
Programmed Cell Death Protein-1 (PD-1)/Programmed Cell Death-Ligand 1 (PD-L1) interaction has a crucial role in maintaining the immune system's self-tolerance by downregulating T cell activation. This mechanism is also used by several types of cancers. By overexpressing the PD-L1 protein, cancer cells can evade the immune response and, therefore, become invisible to the immune system. Herein, we present a detailed characterization of the activity of improved N-terphenylpicolinamides, a class of small molecular blockers targeting the PD-L1 protein disclosed in our recent patent and following patent applications. In our studies, we utilized a cell-based structure-activity relationship (SAR) analysis, which allowed us to discriminate the bioactivity of molecules beyond the detection limits of the protein-based HTRF assay. Our final molecules display high affinity to the molecular target and in vitro bioactivity approaching the activity of a positive control ARB-272572 molecule. An optimized molecule activates primary immune cells, leading to enhanced elimination of cancer cells, as we show in a newly developed co-culture setup. In addition, a co-crystal structure described here confirms the intended mode of binding of the small molecule to PD-L1. Our pharmacokinetics (PK) results rationalize the choice of a representative molecule for further in vivo testing.
{"title":"N-Terphenylpicolinamide derivatives designed to target PD-L1 increase activation and proliferation of T cells, and their cytotoxic properties toward cancer cells","authors":"Damian Muszak, Justyna Kocik-Krol, Julia Zaber, Oskar Kruc, Urszula Palej, Karolina Fijolkowska, Agnieszka Maslanka, Katarzyna Magiera-Mularz, Jacek Plewka, Malgorzata Stec, Marcin Surmiak, Malgorzata Szafarz, Maciej Siedlar, Bogdan Musielak, Radoslaw Kitel, Elzbieta Wyska, Lukasz Skalniak, Ewa Surmiak","doi":"10.1016/j.ejmech.2026.118652","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118652","url":null,"abstract":"Programmed Cell Death Protein-1 (PD-1)/Programmed Cell Death-Ligand 1 (PD-L1) interaction has a crucial role in maintaining the immune system's self-tolerance by downregulating T cell activation. This mechanism is also used by several types of cancers. By overexpressing the PD-L1 protein, cancer cells can evade the immune response and, therefore, become invisible to the immune system. Herein, we present a detailed characterization of the activity of improved N-terphenylpicolinamides, a class of small molecular blockers targeting the PD-L1 protein disclosed in our recent patent and following patent applications. In our studies, we utilized a cell-based structure-activity relationship (SAR) analysis, which allowed us to discriminate the bioactivity of molecules beyond the detection limits of the protein-based HTRF assay. Our final molecules display high affinity to the molecular target and <em>in vitro</em> bioactivity approaching the activity of a positive control ARB-272572 molecule. An optimized molecule activates primary immune cells, leading to enhanced elimination of cancer cells, as we show in a newly developed co-culture setup. In addition, a co-crystal structure described here confirms the intended mode of binding of the small molecule to PD-L1. Our pharmacokinetics (PK) results rationalize the choice of a representative molecule for further <em>in vivo</em> testing.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"311 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135333","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}
Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer lacking estrogen receptor (ER), progesterone receptor (PR), and HER2 expression. Among its heterogeneous subtypes, luminal androgen receptor-positive (LAR) TNBC is driven by androgen signaling and presents limited treatment options. We previously identified dehydrogenase/reductase SDR family member 11 (DHRS11) as a novel enzyme involved in androgen biosynthesis, and demonstrated that Kobochromone A (KC-A), a polyphenol isolated from Carex kobomugi, inhibited androgen-driven proliferation in LAR TNBC cells via DHRS11 inhibition and AR downregulation.In this study, we synthesized 23 structural derivatives of KC-A and identified WH23 as the most potent DHRS11 inhibitor (IC50 = 37 nM). Molecular docking and MM-PBSA analysis revealed that the 2'-hydroxy group of WH23 forms a hydrogen bond with His210 of DHRS11, which was validated by site-directed mutagenesis. WH23 suppressed AR mRNA and protein expression, reduced 11-ketodihydrotestosterone (11KDHT)-induced c-Myc expression, and inhibited proliferation of MDA-MB-453 cells. Additionally, WH23 inhibited PI3K/AKT signaling, reducing phosphorylation of PDK1, AKT, mTOR, and ERK. Capivasertib (Cap), a clinically approved pan-AKT inhibitor, induced DHRS11 expression in MDA-MB-453 cells. Although Cap and WH23 did not show synergistic cytotoxicity in parental cells, Cap-resistant (Cap-R) cells, which exhibited elevated DHRS11 and c-Myc expression, showed significant sensitivity to the combination. In Cap-R cells, the combination of Cap and WH23 significantly induced apoptosis, demonstrating a synergistic anticancer effect.These findings establish WH23 as a dual-acting compound targeting both androgen biosynthesis and AR signaling, with potential to overcome AKT inhibitor resistance in LAR TNBC.
{"title":"Synthesis of potent human DHRS11 inhibitors and their efficacy against androgen-dependent proliferation and sensitivity to AKT inhibitor Capivasertib of triple-negative breast cancer cells","authors":"Yuri Miyamoto, Wakana Hirai, Tomofumi Saka, Masatoshi Tanio, Yudai Kudo, Yuta Yoshino, Yusuke Nakagawa, Nao Kobayashi, Sana Takada, Takuya Okada, Naoki Toyooka, Mahmoud Kandeel, Nobutada Tanaka, Akira Ikari, Satoshi Endo","doi":"10.1016/j.ejmech.2026.118649","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118649","url":null,"abstract":"Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer lacking estrogen receptor (ER), progesterone receptor (PR), and HER2 expression. Among its heterogeneous subtypes, luminal androgen receptor-positive (LAR) TNBC is driven by androgen signaling and presents limited treatment options. We previously identified dehydrogenase/reductase SDR family member 11 (DHRS11) as a novel enzyme involved in androgen biosynthesis, and demonstrated that Kobochromone A (<strong>KC-A</strong>), a polyphenol isolated from <em>Carex kobomugi</em>, inhibited androgen-driven proliferation in LAR TNBC cells via DHRS11 inhibition and AR downregulation.In this study, we synthesized 23 structural derivatives of <strong>KC-A</strong> and identified <strong>WH23</strong> as the most potent DHRS11 inhibitor (IC<sub>50</sub> = 37 nM). Molecular docking and MM-PBSA analysis revealed that the 2'-hydroxy group of <strong>WH23</strong> forms a hydrogen bond with His210 of DHRS11, which was validated by site-directed mutagenesis. <strong>WH23</strong> suppressed AR mRNA and protein expression, reduced 11-ketodihydrotestosterone (11KDHT)-induced c-Myc expression, and inhibited proliferation of MDA-MB-453 cells. Additionally, <strong>WH23</strong> inhibited PI3K/AKT signaling, reducing phosphorylation of PDK1, AKT, mTOR, and ERK. Capivasertib (<strong>Cap</strong>), a clinically approved pan-AKT inhibitor, induced DHRS11 expression in MDA-MB-453 cells. Although <strong>Cap</strong> and <strong>WH23</strong> did not show synergistic cytotoxicity in parental cells, <strong>Cap</strong>-resistant (Cap-R) cells, which exhibited elevated DHRS11 and c-Myc expression, showed significant sensitivity to the combination. In Cap-R cells, the combination of <strong>Cap</strong> and <strong>WH23</strong> significantly induced apoptosis, demonstrating a synergistic anticancer effect.These findings establish <strong>WH23</strong> as a dual-acting compound targeting both androgen biosynthesis and AR signaling, with potential to overcome AKT inhibitor resistance in LAR TNBC.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"89 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122318","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 : 2026-02-05DOI: 10.1016/j.ejmech.2026.118651
Yuanyan Zuo, Yilan Zhao, Genyan Liu, Qi Sun
The γ-aminobutyric acid type A (GABAA) receptor is a principal mediator of fast inhibitory neurotransmission in the central nervous system. Dysfunction of the GABAA receptor (GABAAR) is closely associated with various neuropsychiatric disorders, making it a crucial target for developing therapeutic agents. Recent advances in cryo-electron microscopy (cryo-EM) have enabled direct visualization of subtype-specific conformations, ligand-binding pockets, and gating-associated structural rearrangements of GABAAR, providing a structural basis for mechanism-driven and subtype-selective allosteric modulator design. This review summarizes recent progress in GABAA receptor targeting ligands, with an emphasis on distinct allosteric binding sites, regulatory mechanisms, and subtype-dependent pharmacological profiles. Representative chemical scaffolds are discussed to illustrate structure-based optimization strategies and lead identification approaches informed by high-resolution structural data. Collectively, these advances highlight how structure-resolved insights are reshaping GABAAR drug discovery and enabling the development of next-generation therapeutics with improved efficacy and reduced adverse effects.
{"title":"Recent Advances in GABAA Receptor Targeting Ligands","authors":"Yuanyan Zuo, Yilan Zhao, Genyan Liu, Qi Sun","doi":"10.1016/j.ejmech.2026.118651","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118651","url":null,"abstract":"The γ-aminobutyric acid type A (GABA<sub>A</sub>) receptor is a principal mediator of fast inhibitory neurotransmission in the central nervous system. Dysfunction of the GABA<sub>A</sub> receptor (GABA<sub>A</sub>R) is closely associated with various neuropsychiatric disorders, making it a crucial target for developing therapeutic agents. Recent advances in cryo-electron microscopy (cryo-EM) have enabled direct visualization of subtype-specific conformations, ligand-binding pockets, and gating-associated structural rearrangements of GABA<sub>A</sub>R, providing a structural basis for mechanism-driven and subtype-selective allosteric modulator design. This review summarizes recent progress in GABA<sub>A</sub> receptor targeting ligands, with an emphasis on distinct allosteric binding sites, regulatory mechanisms, and subtype-dependent pharmacological profiles. Representative chemical scaffolds are discussed to illustrate structure-based optimization strategies and lead identification approaches informed by high-resolution structural data. <strong>Collectively, these advances highlight how structure-resolved insights are reshaping GABA</strong><sub><strong>A</strong></sub><strong>R drug discovery and enabling the development of next-generation therapeutics with improved efficacy and reduced adverse effects.</strong>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"30 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122319","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 : 2026-02-05DOI: 10.1016/j.ejmech.2026.118641
Qitao Xiao, Yuxian Wang, Zheyuan Shen, Jun Mo, Cong Li, Rongkuan Jiang, Jingyu Zhang, Yubo Zhou, Xiaowu Dong, Hanlin Wang, Tao Liu
A machine learning-guided strategy, which integrated unsupervised structural clustering to identify diverse scaffolds for molecular hybridization followed by synergistic QSAR and molecular docking screening, identified lead compound 7. Guided by this lead, a series of thieno[2,3-d]pyrimidine derivatives were developed as menin inhibitors through several rounds of rational structural optimization. Among them, compound A13 exhibited potent anti-proliferative activity against MV4-11 cells (0.379 ± 0.182 μM). Besides, mechanistic studies confirmed A13 disrupts menin-MLL interactions, induces cell differentiation, and selectively inhibits MLL-rearranged (MV4-11, MOLM-13) and DNMT3A/NPM1-mutated (OCI-AML3) leukemia cells. The stable binding mode of A13 with menin was further elucidated by molecular dynamics simulations. Moreover, A13 exhibited favorable oral pharmacokinetic properties, characterized by rapid absorption (Tmax = 1.67 h) and high plasma exposure (AUC0–t = 2241 ng·h/mL), demonstrating its potential as a promising candidate for further preclinical development against MLL-rearranged AML.
{"title":"Discovery and Optimization of Menin-MLL Inhibitors Targeting Acute Myeloid Leukemia.","authors":"Qitao Xiao, Yuxian Wang, Zheyuan Shen, Jun Mo, Cong Li, Rongkuan Jiang, Jingyu Zhang, Yubo Zhou, Xiaowu Dong, Hanlin Wang, Tao Liu","doi":"10.1016/j.ejmech.2026.118641","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118641","url":null,"abstract":"A machine learning-guided strategy, which integrated unsupervised structural clustering to identify diverse scaffolds for molecular hybridization followed by synergistic QSAR and molecular docking screening, identified lead compound 7. Guided by this lead, a series of thieno[2,3-d]pyrimidine derivatives were developed as menin inhibitors through several rounds of rational structural optimization. Among them, compound <strong>A13</strong> exhibited potent anti-proliferative activity against MV4-11 cells (0.379 ± 0.182 μM). Besides, mechanistic studies confirmed <strong>A13</strong> disrupts menin-MLL interactions, induces cell differentiation, and selectively inhibits MLL-rearranged (MV4-11, MOLM-13) and DNMT3A/NPM1-mutated (OCI-AML3) leukemia cells. The stable binding mode of A13 with menin was further elucidated by molecular dynamics simulations. Moreover, <strong>A13</strong> exhibited favorable oral pharmacokinetic properties, characterized by rapid absorption (T<sub>max</sub> = 1.67 h) and high plasma exposure (AUC<sub>0–t</sub> = 2241 ng·h/mL), demonstrating its potential as a promising candidate for further preclinical development against MLL-rearranged AML.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"1 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135340","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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