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}
Pub Date : 2026-02-05DOI: 10.1016/j.ejmech.2026.118645
Marine Michon, Sebastien Curpanen, Ombeline Pessey, Robert Thai, Jean-Charles Gaillard, Gaëtan Herbette, Karen Hinsinger, Daniel Gillet, Jean Armengaud, Jean-Christophe Cintrat, Julien Barbier
PROteolysis TArgeting Chimeras are attracting growing interest in pharmaceutical research thanks to their catalytic and irreversible mechanism, which is capable of targeting proteins previously considered "undruggable". These bifunctional molecules hijack the cellular ubiquitin-proteasome system by recruiting E3 ligases (such as CRBN or VHL) to induce the selective degradation of a target protein. Their efficacy has been demonstrated against various disorders and several compounds have reached phase I-III clinical trials, reinforcing their appeal. In the fight against toxins, derivatives of the Retro-2 molecule (active against Shigatoxins, ricin, and various pathogens) have been developed. These molecules act on host cells by disrupting the intracellular trafficking of pathogens, targeting in particular the Sec16A and/or ASNA1 proteins. Our study presents the synthesis and characterization of new chemical probes based on PROTAC technology, combining a CRBN ligand derived from thalidomide, a Retro-2 derivative, and variable-length PEG chain linkers to better understand the mechanism of action of Retro-2-derived molecules. Contrary to initial assumptions, our results do not show proteasome-dependent degradation of the protein targets, but demonstrate that PEG-2 molecules can degrade the translation termination factor GSPT1 despite the normally propitious anchoring of the PEG linker at position 4 of the phthalimide ring. Furthermore, this study shows for the first time that GSPT1 degradation depends on the length of the flexible PEG chain linker.
{"title":"Synthesis and biological evaluation of Retro-2-based PROTACs reveal PEG-linker length and warhead impact on GSPT1 degradation","authors":"Marine Michon, Sebastien Curpanen, Ombeline Pessey, Robert Thai, Jean-Charles Gaillard, Gaëtan Herbette, Karen Hinsinger, Daniel Gillet, Jean Armengaud, Jean-Christophe Cintrat, Julien Barbier","doi":"10.1016/j.ejmech.2026.118645","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118645","url":null,"abstract":"PROteolysis TArgeting Chimeras are attracting growing interest in pharmaceutical research thanks to their catalytic and irreversible mechanism, which is capable of targeting proteins previously considered \"undruggable\". These bifunctional molecules hijack the cellular ubiquitin-proteasome system by recruiting E3 ligases (such as CRBN or VHL) to induce the selective degradation of a target protein. Their efficacy has been demonstrated against various disorders and several compounds have reached phase I-III clinical trials, reinforcing their appeal. In the fight against toxins, derivatives of the Retro-2 molecule (active against Shigatoxins, ricin, and various pathogens) have been developed. These molecules act on host cells by disrupting the intracellular trafficking of pathogens, targeting in particular the Sec16A and/or ASNA1 proteins. Our study presents the synthesis and characterization of new chemical probes based on PROTAC technology, combining a CRBN ligand derived from thalidomide, a Retro-2 derivative, and variable-length PEG chain linkers to better understand the mechanism of action of Retro-2-derived molecules. Contrary to initial assumptions, our results do not show proteasome-dependent degradation of the protein targets, but demonstrate that PEG-2 molecules can degrade the translation termination factor GSPT1 despite the normally propitious anchoring of the PEG linker at position 4 of the phthalimide ring. Furthermore, this study shows for the first time that GSPT1 degradation depends on the length of the flexible PEG chain linker.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"103 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146116103","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.2026.118653
Sadiq Noor Khan, Samira Farhadi, Najeeb Ur Rehman, Sobia Ahsan Halim, Issa S. Al-Amri, Ajmal Khan, Muhammad U. Anwar, René Csuk, Satya Kumar Avula, Ahmed Al-Harrasi
In this study, we report the design, synthesis, and biological evaluation of a new series of triterpenoid metronidazole-linked 1H-1,2,3-triazole conjugates (16–23) as potential targeted therapies. These compounds were screened across a panel of ovarian cancer cell lines. The cytotoxic profiles of all β-AKBA and β-ABA metronidazole–triazole hybrids were evaluated against normal endothelial cells (HUVEC), cisplatin-sensitive ovarian cancer cells (A2780-S), and cisplatin-resistant cells (A2780-CP). Several derivatives showed enhanced cytotoxicity relative to their parent triterpenoids, with compound 21 exhibiting the most favourable selectivity index (SI ≈ 1.61), demonstrating preferential toxicity toward malignant cells while sparing normal cells. The selective cytotoxicity is controlled by reaching an ideal balance of molecular weight, topological polar surface area, hydrogen-bonding characteristics, and nitrogen-rich substituents, according to structure-activity relationship (SAR) studies. Computational docking studies further confirmed that compound 21 displays strong complementarity and robust binding affinity toward PARP6, suggesting a possible mechanism of action through PARP6 modulation. The study provides a promising platform for advancing triterpenoid-based targeted therapeutics in ovarian cancer therapy.
{"title":"Design and Synthesis of Novel Triazole-Metronidazole Boswellic Acid Hybrids for Ovarian Cancer Targeting","authors":"Sadiq Noor Khan, Samira Farhadi, Najeeb Ur Rehman, Sobia Ahsan Halim, Issa S. Al-Amri, Ajmal Khan, Muhammad U. Anwar, René Csuk, Satya Kumar Avula, Ahmed Al-Harrasi","doi":"10.1016/j.ejmech.2026.118653","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118653","url":null,"abstract":"In this study, we report the design, synthesis, and biological evaluation of a new series of triterpenoid metronidazole-linked 1<em>H</em>-1,2,3-triazole conjugates (<strong>16–23</strong>) as potential targeted therapies. These compounds were screened across a panel of ovarian cancer cell lines. The cytotoxic profiles of all <em>β</em>-AKBA and <em>β</em>-ABA metronidazole–triazole hybrids were evaluated against normal endothelial cells (HUVEC), cisplatin-sensitive ovarian cancer cells (A2780-S), and cisplatin-resistant cells (A2780-CP). Several derivatives showed enhanced cytotoxicity relative to their parent triterpenoids, with compound <strong>21</strong> exhibiting the most favourable selectivity index (SI ≈ 1.61), demonstrating preferential toxicity toward malignant cells while sparing normal cells. The selective cytotoxicity is controlled by reaching an ideal balance of molecular weight, topological polar surface area, hydrogen-bonding characteristics, and nitrogen-rich substituents, according to structure-activity relationship (SAR) studies. Computational docking studies further confirmed that compound <strong>21</strong> displays strong complementarity and robust binding affinity toward PARP6, suggesting a possible mechanism of action through PARP6 modulation. The study provides a promising platform for advancing triterpenoid-based targeted therapeutics in ovarian cancer therapy.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"53 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135343","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 : 2026-02-04DOI: 10.1016/j.ejmech.2026.118624
Aylin Berwanger, Konrad Wagner, Simon Both, Andreas M. Kany, Kyana Mazlom, Anna K.H. Hirsch, Alexandra K. Kiemer, Martin Empting
Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2/IMP2) plays a crucial role in the posttranscriptional regulation of gene expression and influences various cellular processes including cell growth, differentiation, and metabolism. Dysregulation of IMP2 has been associated with several diseases, including cancer and metabolic disorders. Targeting IMP2 with small molecules is a promising therapeutic strategy. However, the structural diversity of IMP2-targeting compounds remains limited. In this study, we present a comprehensive screening approach with the aim of identifying new structural classes of compounds that can inhibit IMP2 activity, particularly its binding to the KH34 domain. Screening of a chemically diverse library comprising 10,240 compounds using fluorescence polarization–based assays led to the identification of ten primary actives belonging to five distinct structural classes. After rigorous resynthesis and hit validation, only one compound comprising a sulfonamide scaffold reproducibly inhibited the KH34–RNA interaction in vitro. This hit was further characterized by STD-NMR and in vitro ADME profiling, including solubility, lipophilicity, metabolic stability, plasma protein binding, and cellular permeability. While this sulfonamide-based inhibitor exhibits clear biochemical activity and a defined binding mode at the KH34 RNA-binding interface, its limited cellular permeability and high plasma protein binding currently preclude cellular efficacy. This work identifies a new structural class of IMP2 KH34 inhibitors serving as a starting point for an ongoing hit-to-lead optimization campaign towards next-generation anti-cancer drugs.
{"title":"Identification of a new protein-RNA interaction inhibitor targeting the KH34 region of the Insulin-Like Growth Factor 2 mRNA Binding Protein 2 (IGF2BP2/IMP2)","authors":"Aylin Berwanger, Konrad Wagner, Simon Both, Andreas M. Kany, Kyana Mazlom, Anna K.H. Hirsch, Alexandra K. Kiemer, Martin Empting","doi":"10.1016/j.ejmech.2026.118624","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118624","url":null,"abstract":"Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2/IMP2) plays a crucial role in the posttranscriptional regulation of gene expression and influences various cellular processes including cell growth, differentiation, and metabolism. Dysregulation of IMP2 has been associated with several diseases, including cancer and metabolic disorders. Targeting IMP2 with small molecules is a promising therapeutic strategy. However, the structural diversity of IMP2-targeting compounds remains limited. In this study, we present a comprehensive screening approach with the aim of identifying new structural classes of compounds that can inhibit IMP2 activity, particularly its binding to the KH34 domain. Screening of a chemically diverse library comprising 10,240 compounds using fluorescence polarization–based assays led to the identification of ten primary actives belonging to five distinct structural classes. After rigorous resynthesis and hit validation, only one compound comprising a sulfonamide scaffold reproducibly inhibited the KH34–RNA interaction <em>in vitro</em>. This hit was further characterized by STD-NMR and <em>in vitro</em> ADME profiling, including solubility, lipophilicity, metabolic stability, plasma protein binding, and cellular permeability. While this sulfonamide-based inhibitor exhibits clear biochemical activity and a defined binding mode at the KH34 RNA-binding interface, its limited cellular permeability and high plasma protein binding currently preclude cellular efficacy. This work identifies a new structural class of IMP2 KH34 inhibitors serving as a starting point for an ongoing hit-to-lead optimization campaign towards next-generation anti-cancer drugs.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"39 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135335","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}
Poly-ADP-ribose-polymerase inhibitors (PARPi) hold significant clinical value in the treatment of BRCA-deficient tumors, but their substantial hematological toxicity limits a broader scope of clinical applications. Studies suggest that the toxicity may be associated with selective deficiency between PARP1 and PARP2. In this study, we designed and synthesized a series of inhibitors containing novel pyrrolo[1,2-b]pyridazin-2(1H)-one scaffold selectively targeting PARP1. Among these compounds, YCH3971 exhibited potent inhibiting activity against PARP1 with an IC50 of 7.52 nM, showing a remarkable subtype selectivity compared with PARP2 (> 1000-fold). Also, YCH3971 possessed a strong antiproliferative activity on BRCA mutant MDA-MB-436 cells with an IC50 of 2.10 nM. However, since the oral bioavailability of YCH3971 in rats is only 1.2%, we have not yet initiated in vivo efficacy studies.
{"title":"Design, Synthesis and Biological Evaluation of Novel Pyrrolo[1,2-b]pyridazin-2(1H)-ones as Selective PARP1 Inhibitors for Cancer Therapy","authors":"Qiaolin He, Jing He, Xiajuan Huan, Shanshan Song, Xiaofei Zhang, Qian He, Zehong Miao, Jinxue He, Chunhao Yang","doi":"10.1016/j.ejmech.2026.118650","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118650","url":null,"abstract":"Poly-ADP-ribose-polymerase inhibitors (PARPi) hold significant clinical value in the treatment of BRCA-deficient tumors, but their substantial hematological toxicity limits a broader scope of clinical applications. Studies suggest that the toxicity may be associated with selective deficiency between PARP1 and PARP2. In this study, we designed and synthesized a series of inhibitors containing novel pyrrolo[1,2-<em>b</em>]pyridazin-2(1<em>H</em>)-one scaffold selectively targeting PARP1. Among these compounds, <strong>YCH3971</strong> exhibited potent inhibiting activity against PARP1 with an IC<sub>50</sub> of 7.52 nM, showing a remarkable subtype selectivity compared with PARP2 (> 1000-fold). Also, <strong>YCH3971</strong> possessed a strong antiproliferative activity on BRCA mutant MDA-MB-436 cells with an IC<sub>50</sub> of 2.10 nM. However, since the oral bioavailability of <strong>YCH3971</strong> in rats is only 1.2%, we have not yet initiated in vivo efficacy studies.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"25 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122320","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}
Efficient treatment of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) can be achieved by inhibiting the inflammatory cascade and reducing pulmonary inflammation. A series of novel N-(3-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)amide derivatives were rationally designed and synthesized as cathepsin L (CTSL) inhibitors to reduce the expression of pro-inflammatory cytokines. Among these compounds, B5 exhibited dose-dependent inhibition of pro-inflammatory cytokine production in HBE cells, with IC50 values of 2.51 μM for IL-6 and 1.15 μM for IL-8, without inducing significant cytotoxicity in vitro. In addition, B5 effectively inhibited CTSL enzymatic activity, with an IC50 value of 5.52 μM. In LPS-induced ALI mouse model, treatment with B5 (20 mg/kg) significantly reduced inflammatory cell infiltration into lung tissue, thereby markedly alleviating lung injury. Mechanistic studies revealed that B5 suppresses CTSL maturation, which in turn attenuates activation of the downstream NF-κB and p38 MAPK signaling pathways. Molecular docking further demonstrated that B5 establishes stable binding in the active site of CTSL through multiple noncovalent interactions with key residues Asp162, Cys25, and Glu63. Specifically, the NH linker, the pyrimidine ring, and the amino group participate in hydrogen bonding, π–sulfur interactions, and electrostatic interactions, respectively. These findings indicate that B5 exhibits potent anti-inflammatory activity both in vitro and in vivo and represents a promising lead compound for the treatment of ALI.
{"title":"Design and optimization of N-(3-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)amide derivatives as potent anti-inflammatory agents against LPS-induced acute lung injury","authors":"Zhe Wang, Zhengtong Mao, Chunwei Shen, Renying Wang, Bin Liu, Xingxian Zhang","doi":"10.1016/j.ejmech.2026.118639","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118639","url":null,"abstract":"Efficient treatment of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) can be achieved by inhibiting the inflammatory cascade and reducing pulmonary inflammation. A series of novel <em>N</em>-(3-((4-(1<em>H</em>-indol-3-yl)pyrimidin-2-yl)amino)phenyl)amide derivatives were rationally designed and synthesized as cathepsin L (CTSL) inhibitors to reduce the expression of pro-inflammatory cytokines. Among these compounds, <strong>B5</strong> exhibited dose-dependent inhibition of pro-inflammatory cytokine production in HBE cells, with IC<sub>50</sub> values of 2.51 μM for IL-6 and 1.15 μM for IL-8, without inducing significant cytotoxicity <em>in vitro</em>. In addition, <strong>B5</strong> effectively inhibited CTSL enzymatic activity, with an IC<sub>50</sub> value of 5.52 μM. In LPS-induced ALI mouse model, treatment with <strong>B5</strong> (20 mg/kg) significantly reduced inflammatory cell infiltration into lung tissue, thereby markedly alleviating lung injury. Mechanistic studies revealed that <strong>B5</strong> suppresses CTSL maturation, which in turn attenuates activation of the downstream NF-κB and p38 MAPK signaling pathways. Molecular docking further demonstrated that <strong>B5</strong> establishes stable binding in the active site of CTSL through multiple noncovalent interactions with key residues Asp162, Cys25, and Glu63. Specifically, the NH linker, the pyrimidine ring, and the amino group participate in hydrogen bonding, π–sulfur interactions, and electrostatic interactions, respectively. These findings indicate that <strong>B5</strong> exhibits potent anti-inflammatory activity both <em>in vitro</em> and <em>in vivo</em> and represents a promising lead compound for the treatment of ALI.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"23 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109849","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 : 2026-02-03DOI: 10.1016/j.ejmech.2026.118635
Hyerin Yim, Xiangyang Song, Yue Zhong, Jacqueline Hu, Yan Xiong, Jian Jin
PROteolysis TArgeting Chimera (PROTAC) is a promising modality for targeted protein degradation. Although 600+ E3 ligases exist in the human genome, most PROTACs exploit a very limited set of E3 ligases, primarily CRBN and VHL. In this study, we designed, synthesized and evaluated a series of KRAS-G12D degraders that recruit one of four E3 ligases (CRBN, VHL, DCAF1, or KLHDC2) using a common KRAS-G12D binder derived from the KRAS-G12D inhibitor MRTX1133. Through this structure–activity relationship (SAR) study, we discovered two potent degraders: 30 (CRBN-based) and 41 (VHL-based), both of which effectively degraded KRAS-G12D and suppressed downstream signaling. By introducing a triazole-based VHL ligand, we subsequently discovered 43, which showed improved degradation and antiproliferative activity comparable to a previously reported KRAS-G12D degrader. In contrast, KLHDC2- and DCAF1-based degraders failed to induce KRAS-G12D degradation, potentially due to suboptimal ternary complex formation or insufficient E3 ligase compatibility. These findings highlight the importance of E3 ligase selection in the development of effective KRAS-G12D degraders.
{"title":"Discovery of KRAS-G12D Degraders via Exploration of Various E3 Ligases","authors":"Hyerin Yim, Xiangyang Song, Yue Zhong, Jacqueline Hu, Yan Xiong, Jian Jin","doi":"10.1016/j.ejmech.2026.118635","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118635","url":null,"abstract":"PROteolysis TArgeting Chimera (PROTAC) is a promising modality for targeted protein degradation. Although 600+ E3 ligases exist in the human genome, most PROTACs exploit a very limited set of E3 ligases, primarily CRBN and VHL. In this study, we designed, synthesized and evaluated a series of KRAS-G12D degraders that recruit one of four E3 ligases (CRBN, VHL, DCAF1, or KLHDC2) using a common KRAS-G12D binder derived from the KRAS-G12D inhibitor MRTX1133. Through this structure–activity relationship (SAR) study, we discovered two potent degraders: <strong>30</strong> (CRBN-based) and <strong>41</strong> (VHL-based), both of which effectively degraded KRAS-G12D and suppressed downstream signaling. By introducing a triazole-based VHL ligand, we subsequently discovered <strong>43</strong>, which showed improved degradation and antiproliferative activity comparable to a previously reported KRAS-G12D degrader. In contrast, KLHDC2- and DCAF1-based degraders failed to induce KRAS-G12D degradation, potentially due to suboptimal ternary complex formation or insufficient E3 ligase compatibility. These findings highlight the importance of E3 ligase selection in the development of effective KRAS-G12D degraders.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"39 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109847","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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