54 novel oxazolo [4,3-f]purine derivatives were designed, synthesized, and evaluated for antitumor activity, among which compound 20b exhibited potent activity against several cancer cell lines. Compound 20b inhibited cell metastasis, arrested the cell cycle in the G0/G1 phase, and induced apoptosis in HCT116 cells. Mechanistic studies revealed that 20b increased ROS levels and led to DNA damage, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction in HCT116 cells. Limited proteolysis-small molecule mapping (LiP-SMap), drug affinity responsive target stability (DARTS) assay, cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR) experiments provided evidence that compound 20b bound to PPIA with a KD value of 0.52 μM. siRNA assay indicated that 20b-mediated antiproliferative and antimigration activities were abolished and that the PPIA/MAPK signaling pathway was inhibited when PPIA was silenced in HCT116 cells. Significantly, compound 20b presented significant anticolorectal cancer efficacy in vivo without obvious toxicity. These results indicate that 20b may serve as a novel anticancer agent targeting PPIA, meriting further attention in antitumor drug research.
{"title":"Discovery of Novel Oxazolo[4,3-f]purine Derivatives as Antitumor Agents through PPIA Interaction","authors":"Xian-Jia Li, Meng-Cheng Zhang, Xiang Li, Lu−Lu Guan, Yu-Ru Liang, Er-Jun Hao, Yang Wang, Hai-Ming Guo","doi":"10.1021/acs.jmedchem.4c02819","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02819","url":null,"abstract":"54 novel oxazolo [4,3-<i>f</i>]purine derivatives were designed, synthesized, and evaluated for antitumor activity, among which compound <b>20b</b> exhibited potent activity against several cancer cell lines. Compound <b>20b</b> inhibited cell metastasis, arrested the cell cycle in the G<sub>0</sub>/G<sub>1</sub> phase, and induced apoptosis in HCT116 cells. Mechanistic studies revealed that <b>20b</b> increased ROS levels and led to DNA damage, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction in HCT116 cells. Limited proteolysis-small molecule mapping (LiP-SMap), drug affinity responsive target stability (DARTS) assay, cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR) experiments provided evidence that compound <b>20b</b> bound to PPIA with a KD value of 0.52 μM. siRNA assay indicated that <b>20b</b>-mediated antiproliferative and antimigration activities were abolished and that the PPIA/MAPK signaling pathway was inhibited when PPIA was silenced in HCT116 cells. Significantly, compound <b>20b</b> presented significant anticolorectal cancer efficacy <i>in vivo</i> without obvious toxicity. These results indicate that <b>20b</b> may serve as a novel anticancer agent targeting PPIA, meriting further attention in antitumor drug research.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"10 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-26DOI: 10.1021/acs.jmedchem.4c02774
Peng He, Chengming Wen, Xinyu Zhang, Hang Yin
Cyclic GMP-AMP synthase (cGAS), a critical cytosolic DNA sensor initiating innate immune responses in the presence of cytosolic DNA, is increasingly recognized as a promising therapeutic target for ulcerative colitis (UC). Here, we reported the design, synthesis, structure–activity relationship exploration and biological evaluation of a novel class of CRBN-recruiting cGAS-targeting PROTAC degraders. Among them, TH35 exhibited the most favorable degradation profile, achieving potent and selective degradation of cGAS, and markedly attenuated dsDNA-induced activation of cGAS signaling in both human and murine cells, with minimal cytotoxic effects. In vivo, TH35 demonstrated superior therapeutic efficacy in a dextran sulfate sodium (DSS)-induced mouse model of UC compared to the corresponding cGAS inhibitor, while also displaying acceptable pharmacokinetic properties. Collectively, TH35 as the first CRBN-recruiting cGAS PROTAC holds promise for augmenting anti-inflammatory responses and offers a new avenue for treating cGAS-driven inflammatory diseases.
{"title":"Discovery of a Novel CRBN-Recruiting cGAS PROTAC Degrader for the Treatment of Ulcerative Colitis","authors":"Peng He, Chengming Wen, Xinyu Zhang, Hang Yin","doi":"10.1021/acs.jmedchem.4c02774","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02774","url":null,"abstract":"Cyclic GMP-AMP synthase (cGAS), a critical cytosolic DNA sensor initiating innate immune responses in the presence of cytosolic DNA, is increasingly recognized as a promising therapeutic target for ulcerative colitis (UC). Here, we reported the design, synthesis, structure–activity relationship exploration and biological evaluation of a novel class of CRBN-recruiting cGAS-targeting PROTAC degraders. Among them, <b>TH35</b> exhibited the most favorable degradation profile, achieving potent and selective degradation of cGAS, and markedly attenuated dsDNA-induced activation of cGAS signaling in both human and murine cells, with minimal cytotoxic effects. In vivo, <b>TH35</b> demonstrated superior therapeutic efficacy in a dextran sulfate sodium (DSS)-induced mouse model of UC compared to the corresponding cGAS inhibitor, while also displaying acceptable pharmacokinetic properties. Collectively, <b>TH35</b> as the first CRBN-recruiting cGAS PROTAC holds promise for augmenting anti-inflammatory responses and offers a new avenue for treating cGAS-driven inflammatory diseases.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"82 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-26DOI: 10.1021/acs.jmedchem.4c03170
Yue Zhang, Ying Han, Xuan Li, Min Huang, Piliang Hao, Jingwu Kang
The selectivity of protein kinase inhibitors (PKIs) remains a major challenge in drug discovery. In this study, we present an ultradeep phosphoproteomics approach for assessing PKI selectivity and elucidating mechanisms of action using Zanubrutinib as a model. Two complementary phosphoproteomics strategies were employed: phosphopeptides enriched with Zr4+-IMAC in combination with TiO2 beads were analyzed using data-independent acquisition (DIA), while tyrosine phosphopeptides enriched with SH2-Superbinder were analyzed via data-dependent acquisition (DDA). The comprehensive phosphoproteomic analysis identified that 97 and 316 phosphosites were significantly altered upon Zanubrutinib stimulation in the DDA and DIA data sets, respectively. Bioinformatics analysis of these phosphoproteins provided a detailed selectivity profile of Zanubrutinib, offering insights into its mechanism of action at the molecular level. Compared to existing methods, our approach is more comprehensive, has higher throughput, and is more precise─not only for PKI selectivity assessment but also for broader cell signaling research.
{"title":"Ultradeep Phosphoproteomics for Assessing Protein Kinase Inhibitor Selectivity on a Proteome Scale","authors":"Yue Zhang, Ying Han, Xuan Li, Min Huang, Piliang Hao, Jingwu Kang","doi":"10.1021/acs.jmedchem.4c03170","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03170","url":null,"abstract":"The selectivity of protein kinase inhibitors (PKIs) remains a major challenge in drug discovery. In this study, we present an ultradeep phosphoproteomics approach for assessing PKI selectivity and elucidating mechanisms of action using Zanubrutinib as a model. Two complementary phosphoproteomics strategies were employed: phosphopeptides enriched with Zr<sup>4+</sup>-IMAC in combination with TiO<sub>2</sub> beads were analyzed using data-independent acquisition (DIA), while tyrosine phosphopeptides enriched with SH2-Superbinder were analyzed via data-dependent acquisition (DDA). The comprehensive phosphoproteomic analysis identified that 97 and 316 phosphosites were significantly altered upon Zanubrutinib stimulation in the DDA and DIA data sets, respectively. Bioinformatics analysis of these phosphoproteins provided a detailed selectivity profile of Zanubrutinib, offering insights into its mechanism of action at the molecular level. Compared to existing methods, our approach is more comprehensive, has higher throughput, and is more precise─not only for PKI selectivity assessment but also for broader cell signaling research.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"186 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Photodynamic therapy (PDT) based on supramolecular assembly has been receiving wide attention due to its great potential application in clinical treatment. Herein, we report a supramolecular photoelectron “reservoir” (SPR) constructed by tetracationic boron dipyrromethene (BODIPY)-based macrocycle (BBox·4Cl), doxorubicin (Dox), and tumor-targeted β-cyclodextrin-grafted hyaluronic acid (HACD). Upon irradiation, BBox·4Cl can in situ catalyze nicotinamide adenine dinucleotide (NADH) to continuously generate electrons to inject into SPR, which further transfers electrons to oxygen, inducing highly efficient hydroxyl radical generation even under hypoxia. Synergistically, Dox in SPR as “pump” can be encapsulated by BBox·4Cl and transport photoelectrons between two BODIPY units, while HACD as “sponge” can enrich BBox·4Cl by the electrostatic interaction to concentrate them closer in space, which facilitates intramolecular and intermolecular photoelectron transfer, respectively, and significantly enhances the generation of hydroxyl radicals. Meanwhile, electron replenishment in SPR causes NADH depletion and redox dysfunction, thereby accelerating the apoptosis and achieving highly effective synergistic tumor therapy.
{"title":"In Situ NADH-Activated BODIPY-Based Macrocyclic Supramolecular Photosensitizer for Chemo-Photodynamic Synergistic Tumor Therapy","authors":"Zhuo Lei, Ya-Hui Song, Yuan-Li Leng, Yi-Jun Gu, Miao Yu, Yong Chen, Qilin Yu, Yu Liu","doi":"10.1021/acs.jmedchem.5c00094","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00094","url":null,"abstract":"Photodynamic therapy (PDT) based on supramolecular assembly has been receiving wide attention due to its great potential application in clinical treatment. Herein, we report a supramolecular photoelectron “reservoir” (SPR) constructed by tetracationic boron dipyrromethene (BODIPY)-based macrocycle (<b>BBox·</b>4Cl), doxorubicin (Dox), and tumor-targeted β-cyclodextrin-grafted hyaluronic acid (HACD). Upon irradiation, <b>BBox·</b>4Cl can in situ catalyze nicotinamide adenine dinucleotide (NADH) to continuously generate electrons to inject into SPR, which further transfers electrons to oxygen, inducing highly efficient hydroxyl radical generation even under hypoxia. Synergistically, Dox in SPR as “pump” can be encapsulated by <b>BBox·</b>4Cl and transport photoelectrons between two BODIPY units, while HACD as “sponge” can enrich <b>BBox·</b>4Cl by the electrostatic interaction to concentrate them closer in space, which facilitates intramolecular and intermolecular photoelectron transfer, respectively, and significantly enhances the generation of hydroxyl radicals. Meanwhile, electron replenishment in SPR causes NADH depletion and redox dysfunction, thereby accelerating the apoptosis and achieving highly effective synergistic tumor therapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"12 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rational design of bromodomain (BD)-selective inhibitors could mitigate on-target toxicities associated with pan-BET inhibition but is challenging despite the availability of high-resolution structures. By simultaneously forming water bridges with BD1-specific residues in both the BC ring and the ZA channel, we identified a potent and orally bioavailable BET BD1-selective inhibitor DDO-8958, which exhibited a KD of 5.6 nM for BRD4 BD1 and a 214-fold selectivity for BRD4 BD1 over BD2. The cocrystal structure demonstrated a unique multi-water bridge mechanism involving BD1-specific residues K91- and D145-driven BD1 selectivity. DDO-8958 extensively influenced the oncogene expression and metabolic pathway, including oxidative phosphorylation in MIA PaCa-2. In vivo, DDO-8958 inhibited tumor growth and markedly augmented the therapeutic efficacy of the glycolysis inhibitor 2-DG. These findings illuminate that multi-water bridges enable design of BD1-selective inhibitors and a therapeutic strategy involving combined targeting of BD1-induced epigenetic reprogramming and glycolysis pathways for the management of pancreatic cancer.
{"title":"Multi-Water Bridges Enable Design of BET BD1-Selective Inhibitors for Pancreatic Cancer Therapy","authors":"Xuetao Chen, Wenjing Kang, Tingting Wu, Danyan Cao, Yali Chen, Zhiyan Du, Leixin Yan, Fanying Meng, Xinyue Wang, Qidong You, Bing Xiong, Xiaoke Guo, Zhengyu Jiang","doi":"10.1021/acs.jmedchem.4c03069","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03069","url":null,"abstract":"Rational design of bromodomain (BD)-selective inhibitors could mitigate on-target toxicities associated with pan-BET inhibition but is challenging despite the availability of high-resolution structures. By simultaneously forming water bridges with BD1-specific residues in both the BC ring and the ZA channel, we identified a potent and orally bioavailable BET BD1-selective inhibitor <b>DDO-8958</b>, which exhibited a <i>K</i><sub>D</sub> of 5.6 nM for BRD4 BD1 and a 214-fold selectivity for BRD4 BD1 over BD2. The cocrystal structure demonstrated a unique multi-water bridge mechanism involving BD1-specific residues K91- and D145-driven BD1 selectivity. <b>DDO-8958</b> extensively influenced the oncogene expression and metabolic pathway, including oxidative phosphorylation in MIA PaCa-2. <i>In vivo</i>, <b>DDO-8958</b> inhibited tumor growth and markedly augmented the therapeutic efficacy of the glycolysis inhibitor 2-DG. These findings illuminate that multi-water bridges enable design of BD1-selective inhibitors and a therapeutic strategy involving combined targeting of BD1-induced epigenetic reprogramming and glycolysis pathways for the management of pancreatic cancer.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"1 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-25DOI: 10.1021/acs.jmedchem.4c02605
Marco Banzato, Alberto Furlan, Patrizia Locatelli, Jacopo Sgrignani, Alberto Ongaro, Alessandro Dolmella, Sara De Martin, Stefano Comai, Andrea Cavalli, Charles Inturrisi, Ezio Bettini, Paolo L. Manfredi, Andrea Mattarei
N-Methyl-d-aspartate receptor (NMDAR) is gaining increasing interest as a pharmacological target for the development of fast-acting antidepressants. (S)-Methadone (esmethadone), has recently shown promising efficacy for the treatment of major depressive disorder. However, methods for its enantiopure preparation still rely on complex and expensive resolution procedures. In addition, enantiopure methadone metabolites have never been evaluated for their NMDAR activity. Here, we report the development of a novel chiral pool approach, based on cyclic sulfamidate ring-opening reaction, for the asymmetric synthesis of (R)- and (S)-methadone, and the application of this methodology to the stereodivergent synthesis of 20 enantiopure methadone metabolites. The compounds were evaluated for their NMDAR antagonism and for their affinity toward a series of relevant CNS receptors. Strikingly, N-demethylated (6R)-methadol metabolites retain the higher NMDAR uncompetitive antagonism of (R)-methadone, while presenting lower opioid receptor affinity compared to (S)-methadone. These compounds could represent novel candidates for drug development in CNS disorders.
{"title":"New Synthesis and Pharmacological Evaluation of Enantiomerically Pure (R)- and (S)-Methadone Metabolites as N-Methyl-d-aspartate Receptor Antagonists","authors":"Marco Banzato, Alberto Furlan, Patrizia Locatelli, Jacopo Sgrignani, Alberto Ongaro, Alessandro Dolmella, Sara De Martin, Stefano Comai, Andrea Cavalli, Charles Inturrisi, Ezio Bettini, Paolo L. Manfredi, Andrea Mattarei","doi":"10.1021/acs.jmedchem.4c02605","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02605","url":null,"abstract":"<i>N</i>-Methyl-<span>d</span>-aspartate receptor (NMDAR) is gaining increasing interest as a pharmacological target for the development of fast-acting antidepressants. (<i>S</i>)-Methadone (esmethadone), has recently shown promising efficacy for the treatment of major depressive disorder. However, methods for its enantiopure preparation still rely on complex and expensive resolution procedures. In addition, enantiopure methadone metabolites have never been evaluated for their NMDAR activity. Here, we report the development of a novel chiral pool approach, based on cyclic sulfamidate ring-opening reaction, for the asymmetric synthesis of (<i>R</i>)- and (<i>S</i>)-methadone, and the application of this methodology to the stereodivergent synthesis of 20 enantiopure methadone metabolites. The compounds were evaluated for their NMDAR antagonism and for their affinity toward a series of relevant CNS receptors. Strikingly, <i>N</i>-demethylated (6<i>R</i>)-methadol metabolites retain the higher NMDAR uncompetitive antagonism of (<i>R</i>)-methadone, while presenting lower opioid receptor affinity compared to (<i>S</i>)-methadone. These compounds could represent novel candidates for drug development in CNS disorders.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"17 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-25DOI: 10.1021/acs.jmedchem.4c02873
Ru-Yue Zhang, Zi-Xuan Wang, Meng-Yuan Zhang, Yu-Fan Wang, Si-Li Zhou, Jia-Lu Xu, Wen-Xuan Lin, Tian-Rui Ji, Ya-Dong Chen, Tao Lu, Nian-Guang Li, Zhi-Hao Shi
Mucosa-associated lymphoid tissue protein 1 (MALT1), a cysteine protease and the sole paracaspase in humans, plays a pivotal role in the survival and proliferation of NF-κB-dependent malignant cancers, particularly MALT lymphoma and diffuse large B-cell lymphoma (DLBCL). Dysregulated MALT1 activity is implicated in various malignancies, highlighting its importance as a therapeutic target. This Perspective provides an overview of MALT1’s structural and functional characteristics, summarizes recent advancements in small-molecule inhibitors and degraders targeting this protein, and discusses compound structures, structure–activity relationship (SAR) analyses, and biological activities. We aim to inform future research efforts to enhance the activity, selectivity, and pharmacological properties of MALT1-targeting compounds, establishing a foundational framework for drug development in this critical area of cancer therapy.
{"title":"MALT1 Inhibitors and Degraders: Strategies for NF-κB-Driven Malignancies","authors":"Ru-Yue Zhang, Zi-Xuan Wang, Meng-Yuan Zhang, Yu-Fan Wang, Si-Li Zhou, Jia-Lu Xu, Wen-Xuan Lin, Tian-Rui Ji, Ya-Dong Chen, Tao Lu, Nian-Guang Li, Zhi-Hao Shi","doi":"10.1021/acs.jmedchem.4c02873","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02873","url":null,"abstract":"Mucosa-associated lymphoid tissue protein 1 (MALT1), a cysteine protease and the sole paracaspase in humans, plays a pivotal role in the survival and proliferation of NF-κB-dependent malignant cancers, particularly MALT lymphoma and diffuse large B-cell lymphoma (DLBCL). Dysregulated MALT1 activity is implicated in various malignancies, highlighting its importance as a therapeutic target. This Perspective provides an overview of MALT1’s structural and functional characteristics, summarizes recent advancements in small-molecule inhibitors and degraders targeting this protein, and discusses compound structures, structure–activity relationship (SAR) analyses, and biological activities. We aim to inform future research efforts to enhance the activity, selectivity, and pharmacological properties of MALT1-targeting compounds, establishing a foundational framework for drug development in this critical area of cancer therapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"210 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-25DOI: 10.1021/acs.jmedchem.5c00032
Li Shi, Zhuo Xu, Xiaoyu Chen, Qian Meng, Hu Zhou, Bing Xiong, Naixia Zhang
The heterozygous loss-of-function mutations of USP7 lead to the occurrence of Hao–Fountain syndrome, and chemical activators targeting USP7 could potentially serve as a treatment option for the disease. Here, in this study, two drugs Sertraline and Astemizole were identified to act as the agonists of USP7 by binding to its switching loop region. Moreover, although two compounds and USP7’s self-activation C-terminal peptide (CTP) share the same binding pocket in the enzyme, joint activation toward full-length USP7 was observed for sertraline/astemizole and the CTP. According to the published data and our results, we propose that two chemical activators activate USP7 through interacting with those USP7 molecules with the binding pocket unoccupied by the CTP and thus promote their transition to active conformation. Finally, as anticipated, Sertraline and Astemizole were demonstrated to enhance the enzymatic activities of USP7 pathogenic mutants, and this observation sheds a light on the treatment against Hao–Fountain syndrome.
{"title":"Sertraline and Astemizole Enhance the Deubiquitinase Activity of USP7 by Binding to Its Switching Loop Region","authors":"Li Shi, Zhuo Xu, Xiaoyu Chen, Qian Meng, Hu Zhou, Bing Xiong, Naixia Zhang","doi":"10.1021/acs.jmedchem.5c00032","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00032","url":null,"abstract":"The heterozygous loss-of-function mutations of USP7 lead to the occurrence of Hao–Fountain syndrome, and chemical activators targeting USP7 could potentially serve as a treatment option for the disease. Here, in this study, two drugs Sertraline and Astemizole were identified to act as the agonists of USP7 by binding to its switching loop region. Moreover, although two compounds and USP7’s self-activation C-terminal peptide (CTP) share the same binding pocket in the enzyme, joint activation toward full-length USP7 was observed for sertraline/astemizole and the CTP. According to the published data and our results, we propose that two chemical activators activate USP7 through interacting with those USP7 molecules with the binding pocket unoccupied by the CTP and thus promote their transition to active conformation. Finally, as anticipated, Sertraline and Astemizole were demonstrated to enhance the enzymatic activities of USP7 pathogenic mutants, and this observation sheds a light on the treatment against Hao–Fountain syndrome.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"12 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-25DOI: 10.1021/acs.jmedchem.4c02666
Mingyang Hu, Yuwen Li, Lu Zhao, Sina Cha, Yuxin Fang, Chenyu Xue, Na Dong
The rise of antimicrobial resistance (AMR) in Gram-negative bacteria, including Escherichia coli (E. coli), poses a major public health threat. This study aimed to address the limitations of existing antimicrobial peptides (AMPs) by designing hybrid peptides with enhanced targeting and antibacterial potency. Eight heptapeptide sequences were identified through phage display screening and hybridized with WP (WKKIWKPGIKKWIK), a peptide exhibiting weak antimicrobial activity against Gram-negative bacteria. The hybrid peptides were systematically evaluated for their antimicrobial activity, specificity, and biocompatibility. The hybrid peptide SWP exhibited superior antibacterial activity, particularly against E. coli K88 (TI = 2.378), and demonstrated specific binding to thymidylate kinase (TMK), a key bacterial enzyme. In vivo studies employing a mouse peritonitis model confirmed SWP’s ability to reduce bacterial loads and mitigate tissue damage while maintaining excellent biocompatibility. These findings underscore SWP as a promising candidate for the development of targeted antimicrobial agents with enhanced specificity and stability for Gram-negative pathogens.
{"title":"Thymidylate Kinase-Targeted Antimicrobial Peptides via Phage Display: A Novel Strategy against Gram-Negative Bacteria","authors":"Mingyang Hu, Yuwen Li, Lu Zhao, Sina Cha, Yuxin Fang, Chenyu Xue, Na Dong","doi":"10.1021/acs.jmedchem.4c02666","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02666","url":null,"abstract":"The rise of antimicrobial resistance (AMR) in Gram-negative bacteria, including <i>Escherichia coli</i> (<i>E. coli</i>), poses a major public health threat. This study aimed to address the limitations of existing antimicrobial peptides (AMPs) by designing hybrid peptides with enhanced targeting and antibacterial potency. Eight heptapeptide sequences were identified through phage display screening and hybridized with WP (WKKIWKPGIKKWIK), a peptide exhibiting weak antimicrobial activity against Gram-negative bacteria. The hybrid peptides were systematically evaluated for their antimicrobial activity, specificity, and biocompatibility. The hybrid peptide SWP exhibited superior antibacterial activity, particularly against <i>E. coli</i> K88 (TI = 2.378), and demonstrated specific binding to thymidylate kinase (TMK), a key bacterial enzyme. <i>In vivo</i> studies employing a mouse peritonitis model confirmed SWP’s ability to reduce bacterial loads and mitigate tissue damage while maintaining excellent biocompatibility. These findings underscore SWP as a promising candidate for the development of targeted antimicrobial agents with enhanced specificity and stability for Gram-negative pathogens.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"31 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-24DOI: 10.1021/acs.jmedchem.5c00373
Yuxi Wang, Zelin Hu, Junbiao Chang, Bin Yu
Advances in machine learning algorithms and big data processing capabilities have propelled artificial intelligence (AI) to the forefront, with its applications in drug discovery rapidly increasing. A report from McKinsey & Company indicates that the use of AI can help pharmaceutical companies save 30 to 50% in drug development costs and increase the pipeline speed by over 20%. (1) AI technology is becoming increasingly common from drug discovery to clinical trials. First, AI can quickly screen potential active compounds using machine learning and deep learning algorithms, guiding hit-to-lead optimization to improve therapeutic efficacy and reduce toxicity, significantly enhancing the efficiency of drug discovery. Second, AI-driven predictive models can enhance the success rate of experiments, reduce research and development (R&D) costs, and even change a drug’s behavior in the body, including its pharmacokinetics (PK) and pharmacodynamics (PD), to optimize dosage and dosing regimens. By integrating expertise from various disciplines, it enables the derivation of novel conclusions, producing forward-looking results in traditionally empirical areas. Furthermore, AI has driven the development of personalized medicine, bringing significant transformations and opportunities for the future of healthcare. Drug discovery and development is the most advanced area of AI, with numerous breakthroughs already achieved (Figure 1A). For instance, Alex Zhavoronkov’s team developed a deep generative model, generative tensorial reinforcement learning (GENTRL) for <i>de novo</i> small molecule design. (2) The model combines reinforcement learning, variational inference, and tensor decompositions for rapid generation and optimization of potentially pharmacologically active compounds. GENTRL uses three layers of self-organizing mappings (SOMs) to generate innovative DDR1 inhibitors, and these small molecules then undergo multiple screenings and optimizations, resulting in six candidate compounds in just 21 days, with four showing potent biological activity. Even more surprisingly, ISM001-055AI, a first-in-class small molecule inhibitor developed by generative AI technology, shows positive results in a phase IIa clinical trial for treating idiopathic pulmonary fibrosis (IPF). (3) In September 2024, Insilico Medicine announced the results of a Phase IIa clinical trial of ISM001-055. The trial, which enrolled 71 IPF patients across 21 clinical research centers in China, demonstrated that ISM001-055 had a favorable safety profile at all dose levels and exhibited a dose-dependent trend of efficacy in forced vital capacity (FVC), an important measure of lung function in IPF patients. The improvement in lung function in just 12 weeks brings great hope to IPF patients. The success of ISM001-055 showcases the huge potential of AI in drug discovery and development, paving the way for larger-scale trials in the future. Fang’s team recently developed a robotic system fo
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