Pub Date : 2025-04-22DOI: 10.1021/acs.jmedchem.5c00998
Alex G. Waterson
Alongside significant recent advancements in drugging an historically notorious oncogene, scientists continue to uncover new ways to target KRAS. This viewpoint summarizes the newly reported discovery of a novel chemical template that features the ability to tailor inhibition to different activation states of nucleotide-bound KRAS from the same scaffold.
{"title":"Switching It up with New KRAS Inhibitors","authors":"Alex G. Waterson","doi":"10.1021/acs.jmedchem.5c00998","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00998","url":null,"abstract":"Alongside significant recent advancements in drugging an historically notorious oncogene, scientists continue to uncover new ways to target KRAS. This viewpoint summarizes the newly reported discovery of a novel chemical template that features the ability to tailor inhibition to different activation states of nucleotide-bound KRAS from the same scaffold.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"7 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858196","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 : 2025-04-22DOI: 10.1021/acs.jmedchem.5c00396
Robin Kryštůfek, Václav Verner, Pavel Šácha, Martin Hadzima, Filip Trajhan, Jana Starková, Eva Tloušt’ová, Alexandra Dvořáková, Adam Pecina, Jiří Brynda, Karel Chalupský, Miroslav Hájek, Michael J. Boucher, Pavel Majer, Jan Řezáč, Hiten D. Madhani, Charles S. Craik, Jan Konvalinka
Macrocyclic inhibitors have emerged as a privileged scaffold in medicinal chemistry, offering enhanced selectivity, stability, and pharmacokinetic profiles compared to their linear counterparts. Here, we describe a novel, on-resin macrocyclization strategy for the synthesis of potent inhibitors targeting the secreted protease Major Aspartyl Peptidase 1 in Cryptococcus neoformans, a pathogen responsible for life-threatening fungal infections. By employing diverse aliphatic linkers and statine-based transition-state mimics, we constructed a focused library of 624 macrocyclic compounds. Screening identified several subnanomolar inhibitors with desirable pharmacokinetic and antifungal properties. Lead compound 25 exhibited a Ki of 180 pM, significant selectivity against host proteases, and potent antifungal activity in culture. The streamlined synthetic approach not only yielded drug-like macrocycles with potential in antifungal therapy but also provided insights into structure–activity relationships that can inform broader applications of macrocyclization in drug discovery.
{"title":"On-Resin Assembly of Macrocyclic Inhibitors of Cryptococcus neoformans May1: A Pathway to Potent Antifungal Agents","authors":"Robin Kryštůfek, Václav Verner, Pavel Šácha, Martin Hadzima, Filip Trajhan, Jana Starková, Eva Tloušt’ová, Alexandra Dvořáková, Adam Pecina, Jiří Brynda, Karel Chalupský, Miroslav Hájek, Michael J. Boucher, Pavel Majer, Jan Řezáč, Hiten D. Madhani, Charles S. Craik, Jan Konvalinka","doi":"10.1021/acs.jmedchem.5c00396","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00396","url":null,"abstract":"Macrocyclic inhibitors have emerged as a privileged scaffold in medicinal chemistry, offering enhanced selectivity, stability, and pharmacokinetic profiles compared to their linear counterparts. Here, we describe a novel, on-resin macrocyclization strategy for the synthesis of potent inhibitors targeting the secreted protease Major Aspartyl Peptidase 1 in <i>Cryptococcus neoformans</i>, a pathogen responsible for life-threatening fungal infections. By employing diverse aliphatic linkers and statine-based transition-state mimics, we constructed a focused library of 624 macrocyclic compounds. Screening identified several subnanomolar inhibitors with desirable pharmacokinetic and antifungal properties. Lead compound <b>25</b> exhibited a <i>K</i><sub>i</sub> of 180 pM, significant selectivity against host proteases, and potent antifungal activity in culture. The streamlined synthetic approach not only yielded drug-like macrocycles with potential in antifungal therapy but also provided insights into structure–activity relationships that can inform broader applications of macrocyclization in drug discovery.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"51 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862502","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}
Replace the error image in Figure 3(a) with the original, correctly labeled data set for compound 10 (24 h treatment). The original image used in this panel was inadvertently incorrect due to a technical oversight during figure assembly. This error does not impact the scientific conclusions of our study, nor does it undermine its reproducibility. We sincerely apologize for this oversight and are committed to taking full responsibility for maintaining the accuracy of all our published work. The correct version of Figure 3 is shown below. Figure 3. (a) Migration inhibition on HeLa cells by compounds at 0.1 μM after 24 h treatment. (b) Invasion suppression on HeLa cell by compounds at 0.1 μM after 24 h treatment. (c) Statistical analysis of cell mobility. (d) Statistical analysis of cell invasion. ***P < 0.001, compared with control group. This article has not yet been cited by other publications.
{"title":"Correction to “Novel Indoleamine-2,3-dioxygenase-Targeted Pt(IV) Prodrugs Regulate the Tumor Immune Microenvironment to Achieve Chemoimmunotherapy In Vitro and In Vivo”","authors":"Zhe Li, Xiao-Meng Liu, Fei Tan, Jia-Qian Wang, Xin Qiao, Yu-Kuan Feng, Jing-Yuan Xu, Ji-Hui Hao","doi":"10.1021/acs.jmedchem.5c01059","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01059","url":null,"abstract":"Replace the error image in Figure 3(a) with the original, correctly labeled data set for compound <b>10</b> (24 h treatment). The original image used in this panel was inadvertently incorrect due to a technical oversight during figure assembly. This error does not impact the scientific conclusions of our study, nor does it undermine its reproducibility. We sincerely apologize for this oversight and are committed to taking full responsibility for maintaining the accuracy of all our published work. The correct version of Figure 3 is shown below. Figure 3. (a) Migration inhibition on HeLa cells by compounds at 0.1 μM after 24 h treatment. (b) Invasion suppression on HeLa cell by compounds at 0.1 μM after 24 h treatment. (c) Statistical analysis of cell mobility. (d) Statistical analysis of cell invasion. ***<i>P</i> < 0.001, compared with control group. This article has not yet been cited by other publications.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"38 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862500","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 : 2025-04-21DOI: 10.1021/acs.jmedchem.4c03132
Asaad Gammal, Taher Nassar, Yael Soae, Noam Freeman, Amit Badihi, Saja Baraghithy, Alina Nemirovski, Joseph Tam, Simon Benita
The development of peripherally selective cannabinoid-1 receptor (CB1R) antagonists offers a promising strategy for obesity treatment. Here, we evaluated the efficacy of novel tricyclic CB1R antagonists, focusing on BNS808. Our findings demonstrate that BNS808 exhibits robust CB1R antagonism with notable CB2R selectivity, minimal brain penetration, and potent in vitro and in vivo efficacy. The compound’s high plasma protein binding reduces free drug availability for CNS entry, enhancing safety and minimizing drug–drug interactions. In diet-induced obese mice, BNS808 effectively reduced body weight, adiposity, liver triglycerides, and liver enzymes, supporting its peripherally mediated action. These results highlight BNS808 as a promising candidate for obesity treatment. Additionally, our novel library of peripherally selective CB1R antagonists provides a strong foundation for future drug development. With further refinement, BNS808 holds significant clinical potential to address the global obesity epidemic.
{"title":"Synthesis and Pharmacological Characterization of Novel Peripheral Cannabinoid-1 Receptor Blockers Based on a Tricyclic Scaffold","authors":"Asaad Gammal, Taher Nassar, Yael Soae, Noam Freeman, Amit Badihi, Saja Baraghithy, Alina Nemirovski, Joseph Tam, Simon Benita","doi":"10.1021/acs.jmedchem.4c03132","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03132","url":null,"abstract":"The development of peripherally selective cannabinoid-1 receptor (CB<sub>1</sub>R) antagonists offers a promising strategy for obesity treatment. Here, we evaluated the efficacy of novel tricyclic CB<sub>1</sub>R antagonists, focusing on BNS808. Our findings demonstrate that BNS808 exhibits robust CB<sub>1</sub>R antagonism with notable CB<sub>2</sub>R selectivity, minimal brain penetration, and potent in vitro and in vivo efficacy. The compound’s high plasma protein binding reduces free drug availability for CNS entry, enhancing safety and minimizing drug–drug interactions. In diet-induced obese mice, BNS808 effectively reduced body weight, adiposity, liver triglycerides, and liver enzymes, supporting its peripherally mediated action. These results highlight BNS808 as a promising candidate for obesity treatment. Additionally, our novel library of peripherally selective CB<sub>1</sub>R antagonists provides a strong foundation for future drug development. With further refinement, BNS808 holds significant clinical potential to address the global obesity epidemic.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"46 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858197","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}
Gastric cancer is one of the major health threats to human beings and has a low response rate to emerging immunotherapy. We herein reported a novel indole-based LSD1-targeted antigastric agent 7ae, which was able to enhance the sensitivity of gastric cancer cells to a T-cell-mediated immune response. It exhibited potent LSD1 inhibitory activity (IC50 = 0.080 ± 0.002 μM) and reduced the expression of PD-L1, which in turn promoted the T-cell killing response in gastric cancer cells. As a result, 7ae acted as an active LSD1 inhibitor, exerting excellent anti-invasion and anti-migration effects in gastric cancer cells and leading to significant suppression of the growth of xenograft gastric tumors without obvious toxicity in vivo. Collectively, 7ae has been demonstrated to be a novel, potent LSD1 inhibitor with the potential to be used as an antigastric agent, as well as a useful tool compound for exploratory studies of T-cell-mediated immunity and/or immunotherapy in gastric cancer.
{"title":"The Exploration of Indole-Based LSD1-Targeted Inhibitors for Enhanced Immune Response in Gastric Cancer via the PD-L1/PD-1 Axis","authors":"Hang Zhang, Yujie Zhang, Yinping Geng, Xuanlong Zhen, Xiaodi Wang, Qiange Yin, Peng Zhang, Yuanyuan Li, Mengzhen Zhang, Yi-chao Zheng, Bing-rui Liu, Hui-min Liu, Hai-wei Xu","doi":"10.1021/acs.jmedchem.4c02851","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02851","url":null,"abstract":"Gastric cancer is one of the major health threats to human beings and has a low response rate to emerging immunotherapy. We herein reported a novel indole-based LSD1-targeted antigastric agent <b>7ae</b>, which was able to enhance the sensitivity of gastric cancer cells to a T-cell-mediated immune response. It exhibited potent LSD1 inhibitory activity (IC<sub>50</sub> = 0.080 ± 0.002 μM) and reduced the expression of PD-L1, which in turn promoted the T-cell killing response in gastric cancer cells. As a result, <b>7ae</b> acted as an active LSD1 inhibitor, exerting excellent anti-invasion and anti-migration effects in gastric cancer cells and leading to significant suppression of the growth of xenograft gastric tumors without obvious toxicity <i>in vivo.</i> Collectively, <b>7ae</b> has been demonstrated to be a novel, potent LSD1 inhibitor with the potential to be used as an antigastric agent, as well as a useful tool compound for exploratory studies of T-cell-mediated immunity and/or immunotherapy in gastric cancer.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"11 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143853645","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 : 2025-04-21DOI: 10.1021/acs.jmedchem.5c00242
Guangxin Dong, Qijun Ye, Wenwen Li, Shaofeng Zhang, Zhenyu Yang, Rui Zhang, Ta Deng, Haiyan Li, Yong Zhang, Xiaojie Zhang, Shucheng He, Daoheng Zhou, Juan Zhang, Peng He, Zhou Yu, Yi Li
Glucagon-like peptide-1 receptor (GLP-1R) holds pivotal importance as a therapeutic target for type 2 diabetes (T2D) and obesity. Several oral small-molecule agonists targeting GLP-1R have been developed to date. Nevertheless, these agonists suffer from several limitations, including low potency, poor pharmacokinetics, and unfavorable safety profiles. Here, we report the discovery of compound 29 (DA-302168S), which exhibits higher potency both in vitro/invivo while mitigating the risk of drug–drug interaction compared to other reported candidate compounds. Preclinical studies show full efficacy in cAMP activation, glucose reduction, and appetite suppression. Safety assessments reveal minimal risks with hERG IC50 > 30 μM and no significant off-target toxicity. Its favorable pharmacokinetics support once-daily oral dosing, improving patient compliance. These findings suggest that compound 29 offers a promising therapeutic option for the management of T2D and obesity. Notably, it has successfully completed phase I clinical trials and is currently undergoing phase II clinical trials.
{"title":"Discovery and Evaluation of DA-302168S as an Efficacious Oral Small-Molecule Glucagon-Like Peptide-1 Receptor Agonist","authors":"Guangxin Dong, Qijun Ye, Wenwen Li, Shaofeng Zhang, Zhenyu Yang, Rui Zhang, Ta Deng, Haiyan Li, Yong Zhang, Xiaojie Zhang, Shucheng He, Daoheng Zhou, Juan Zhang, Peng He, Zhou Yu, Yi Li","doi":"10.1021/acs.jmedchem.5c00242","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00242","url":null,"abstract":"Glucagon-like peptide-1 receptor (GLP-1R) holds pivotal importance as a therapeutic target for type 2 diabetes (T2D) and obesity. Several oral small-molecule agonists targeting GLP-1R have been developed to date. Nevertheless, these agonists suffer from several limitations, including low potency, poor pharmacokinetics, and unfavorable safety profiles. Here, we report the discovery of compound <b>29</b> (DA-302168S), which exhibits higher potency both <i>in vitro</i>/<i>in</i> <i>vivo</i> while mitigating the risk of drug–drug interaction compared to other reported candidate compounds. Preclinical studies show full efficacy in cAMP activation, glucose reduction, and appetite suppression. Safety assessments reveal minimal risks with hERG IC<sub>50</sub> > 30 μM and no significant off-target toxicity. Its favorable pharmacokinetics support once-daily oral dosing, improving patient compliance. These findings suggest that compound <b>29</b> offers a promising therapeutic option for the management of T2D and obesity. Notably, it has successfully completed phase I clinical trials and is currently undergoing phase II clinical trials.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"41 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143853646","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 : 2025-04-20DOI: 10.1021/acs.jmedchem.4c03057
Long Tian, Taoran Wang, Liang Luan, Zhao Meng, Jiaqi Han, Chunhui Zhao, Yijie Xu, Chunlan Zeng, Weifeng Ye, Shuyuan Jiang, Li Zhang, Jiye Yin, Qingbin Meng, Song Li
Antimicrobial peptides (AMPs) are considered promising agents to solve the problem of antibiotic resistance due to their unique membrane-disruption mechanism. In this research, de novo terminally symmetric β-turn AMPs were designed by combining the β-turn sequences derived from Tritrpticin with alternately arranged cationic and hydrophobic amino acid sequences. The structure–activity relationship of the peptides was studied. Among the designed peptides, P-07 (KIKIKPWWWPKIKIK-NH2) exhibited potent antimicrobial activity against all the tested bacterial strains, showing the highest bacterial selectivity, relatively low cytotoxicity, high bactericidal efficiency, and low potential to induce bacterial resistance. The antimicrobial mechanisms of P-07 involving membrane-disruption and lipopolysaccharide-binding were proven. Moreover, the in vivo studies confirmed the wound-healing ability of P-07 using a mice bacteria-infected full-thickness wound model. Taken together, P-07 showed great promise in the treatment of multidrug-resistant bacterial infections.
{"title":"Terminally Symmetric β-Turn Peptides for Multidrug-Resistant Bacterial Infections","authors":"Long Tian, Taoran Wang, Liang Luan, Zhao Meng, Jiaqi Han, Chunhui Zhao, Yijie Xu, Chunlan Zeng, Weifeng Ye, Shuyuan Jiang, Li Zhang, Jiye Yin, Qingbin Meng, Song Li","doi":"10.1021/acs.jmedchem.4c03057","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03057","url":null,"abstract":"Antimicrobial peptides (AMPs) are considered promising agents to solve the problem of antibiotic resistance due to their unique membrane-disruption mechanism. In this research, de novo terminally symmetric β-turn AMPs were designed by combining the β-turn sequences derived from Tritrpticin with alternately arranged cationic and hydrophobic amino acid sequences. The structure–activity relationship of the peptides was studied. Among the designed peptides, P-07 (KIKIKPWWWPKIKIK-NH<sub>2</sub>) exhibited potent antimicrobial activity against all the tested bacterial strains, showing the highest bacterial selectivity, relatively low cytotoxicity, high bactericidal efficiency, and low potential to induce bacterial resistance. The antimicrobial mechanisms of P-07 involving membrane-disruption and lipopolysaccharide-binding were proven. Moreover, the in vivo studies confirmed the wound-healing ability of P-07 using a mice bacteria-infected full-thickness wound model. Taken together, P-07 showed great promise in the treatment of multidrug-resistant bacterial infections.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"108 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143853648","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 : 2025-04-20DOI: 10.1021/acs.jmedchem.4c02912
Russell G. Fritzemeier, Nicholas S. Akins, Paul J. Arcoria, Srinu Paladugu, Elijah Z. Ullman, James Allen, Rehan Sheikh, Kelsey A. Nocilla, Ellington D. McDaniels, Emanuel M. Coleman, Pantelis Antonoudiou, Michael P. D’Erasmo, Perry Bartsch, Savita K. Sharma, Jamie Maguire, Stephen F. Traynelis, Dennis C. Liotta
Positive allosteric modulators (PAMs) of the N-methyl-d-aspartate receptor (NMDAR) have been proposed as therapeutics in several neuropsychiatric indications, including schizophrenia, depression, cognitive dysfunction, and anxiety. In particular, GluN2D-containing NMDARs are highly expressed in inhibitory interneurons and are a target of interest for drug development. Toward that end, we describe our investigation into the GluN2-selective EU 1622 series of PAMs that enhance receptor efficacy, increase agonist potency, prolong deactivation time course, reduce single channel conductance, and limit calcium influx. Through SAR studies of the amide, aryl, and thiophene side chains, we identified analogues with submicromolar potency that preferentially potentiate GluN2B-, GluN2C-, and GluN2D-containing NMDARs. Elaboration of the thiophene side chain to block metabolism resulted in the discovery of EU 1622-240 (25b) with improved metabolic stability, oral bioavailability, and CNS penetration in rodents. Consequently, we present data with EU 1622-240 showing the promising properties of this series as a biased GluN2 potentiator.
N-甲基-d-天冬氨酸受体（NMDAR）的正性异位调节剂（PAMs）已被提议作为治疗精神分裂症、抑郁症、认知功能障碍和焦虑症等多种神经精神疾病的药物。特别是，含 GluN2D 的 NMDAR 在抑制性中间神经元中高度表达，是药物开发的兴趣靶点。为此，我们介绍了我们对 GluN2 选择性 EU 1622 系列 PAM 的研究，这些 PAM 可增强受体功效、提高激动剂效力、延长失活时间过程、降低单通道电导和限制钙离子流入。通过对酰胺、芳基和噻吩侧链的 SAR 研究，我们发现了具有亚摩尔效力的类似物，它们能优先增效含 GluN2B、GluN2C 和 GluN2D 的 NMDAR。为了阻止代谢，我们对噻吩侧链进行了精心设计，最终发现了 EU 1622-240（25b），它在啮齿动物体内的代谢稳定性、口服生物利用度和中枢神经系统穿透性都得到了改善。因此，我们展示了 EU 1622-240 的数据，这些数据表明该系列药物作为一种偏向 GluN2 的增效剂具有良好的特性。
{"title":"Thienopyrimidinone Derivatives as a GluN2B/C/D Biased, Positive Allosteric Modulator of the N-Methyl-d-Aspartate Receptor","authors":"Russell G. Fritzemeier, Nicholas S. Akins, Paul J. Arcoria, Srinu Paladugu, Elijah Z. Ullman, James Allen, Rehan Sheikh, Kelsey A. Nocilla, Ellington D. McDaniels, Emanuel M. Coleman, Pantelis Antonoudiou, Michael P. D’Erasmo, Perry Bartsch, Savita K. Sharma, Jamie Maguire, Stephen F. Traynelis, Dennis C. Liotta","doi":"10.1021/acs.jmedchem.4c02912","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02912","url":null,"abstract":"Positive allosteric modulators (PAMs) of the <i>N</i>-methyl-<span>d</span>-aspartate receptor (NMDAR) have been proposed as therapeutics in several neuropsychiatric indications, including schizophrenia, depression, cognitive dysfunction, and anxiety. In particular, GluN2D-containing NMDARs are highly expressed in inhibitory interneurons and are a target of interest for drug development. Toward that end, we describe our investigation into the GluN2-selective EU 1622 series of PAMs that enhance receptor efficacy, increase agonist potency, prolong deactivation time course, reduce single channel conductance, and limit calcium influx. Through SAR studies of the amide, aryl, and thiophene side chains, we identified analogues with submicromolar potency that preferentially potentiate GluN2B-, GluN2C-, and GluN2D-containing NMDARs. Elaboration of the thiophene side chain to block metabolism resulted in the discovery of <b>EU 1622-240</b> (<b>25b</b>) with improved metabolic stability, oral bioavailability, and CNS penetration in rodents. Consequently, we present data with <b>EU 1622-240</b> showing the promising properties of this series as a biased GluN2 potentiator.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"47 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143853647","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 : 2025-04-19DOI: 10.1021/acs.jmedchem.5c00485
Cody A. Loy, Eslam M. H. Ali, Laurence J. Seabrook, Timothy J. Harris, Jr, Kate A. Kragness, Lauren Albrecht, Darci J. Trader
The development of targeted protein degradation by recruiting a protein of interest to a ubiquitin ligase to facilitate its degradation has become a powerful therapeutic tool. The potential of this approach is limited to proteins that can be readily ubiquitinated and relies on having a ligand with the various E3 ligases. Here, we describe a new methodology for targeted protein degradation that directly recruits a protein of interest to the proteasome for degradation. We generated bifunctional molecules that incorporate a small molecule ligand into a subunit on the 26S proteasome that recruits the protein directly for degradation. ByeTAC degradation requires binding to Rpn-13, a nonessential ubiquitin receptor of the 26S proteasome, and the protein of interest and does not have to rely on the E ligase cascade for ubiquitination. The ByeTAC methodology demonstrates the application of directly recruiting a protein to the proteasome via interactions with Rpn-13 for degradation.
{"title":"ByeTAC: Bypassing E-Ligase-Targeting Chimeras for Direct Proteasome Degradation","authors":"Cody A. Loy, Eslam M. H. Ali, Laurence J. Seabrook, Timothy J. Harris, Jr, Kate A. Kragness, Lauren Albrecht, Darci J. Trader","doi":"10.1021/acs.jmedchem.5c00485","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00485","url":null,"abstract":"The development of targeted protein degradation by recruiting a protein of interest to a ubiquitin ligase to facilitate its degradation has become a powerful therapeutic tool. The potential of this approach is limited to proteins that can be readily ubiquitinated and relies on having a ligand with the various E3 ligases. Here, we describe a new methodology for targeted protein degradation that directly recruits a protein of interest to the proteasome for degradation. We generated bifunctional molecules that incorporate a small molecule ligand into a subunit on the 26S proteasome that recruits the protein directly for degradation. ByeTAC degradation requires binding to Rpn-13, a nonessential ubiquitin receptor of the 26S proteasome, and the protein of interest and does not have to rely on the E ligase cascade for ubiquitination. The ByeTAC methodology demonstrates the application of directly recruiting a protein to the proteasome via interactions with Rpn-13 for degradation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"135 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143849912","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 : 2025-04-17DOI: 10.1021/acs.jmedchem.5c00546
Ziqian Zhang, Xilan Ma, Wei Pan, Xiaoshun Li, Yanyan Li, Nan Fang, Xin Yin, Longlong Yang, Qi Hou, Dezhi Yang, Tengfei Ji, Ruifang Zheng, Mingbao Lin
Aplastic anemia (AA) is a refractory hematological disease with limited therapeutic effectiveness and serious treatment-related side effects. Cytotoxic T lymphocytes (CTLs) play a key role in AA pathogenesis. In our previous study, sinomenine derivative 3a was obtained, which demonstrated potential anti-AA activity by targeting CTLs with low toxicity. In this study, a novel metabolite, 3a-M1, was identified with optimized bioavailability from 3a metabolism, which exhibited a more notable effect in alleviating anemia symptoms, suppressing bone marrow CTLs activation, and improving hematopoietic function in immune-mediated bone marrow failure mouse models. In vitro experiments demonstrated that 3a-M1 directly inhibited CTLs activation and their killing function; the underlying mechanism was at least in part mediated by the selective ferroptosis of overactivated CTLs via the IP3R/ORAI pathway. These findings suggest that 3a-M1 represents a novel potential therapeutic agent for AA treatment and ferroptosis may serve as a promising target on CTLs for AA therapy.
{"title":"A Novel Compound 3a-M1, from Metabolites of Sinomenine Derivative 3a, Exerts Potent Anti-Aplastic Anemia Activity via IP3R/ORAI-Mediated CTL Ferroptosis","authors":"Ziqian Zhang, Xilan Ma, Wei Pan, Xiaoshun Li, Yanyan Li, Nan Fang, Xin Yin, Longlong Yang, Qi Hou, Dezhi Yang, Tengfei Ji, Ruifang Zheng, Mingbao Lin","doi":"10.1021/acs.jmedchem.5c00546","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00546","url":null,"abstract":"Aplastic anemia (AA) is a refractory hematological disease with limited therapeutic effectiveness and serious treatment-related side effects. Cytotoxic T lymphocytes (CTLs) play a key role in AA pathogenesis. In our previous study, sinomenine derivative 3a was obtained, which demonstrated potential anti-AA activity by targeting CTLs with low toxicity. In this study, a novel metabolite, 3a-M1, was identified with optimized bioavailability from 3a metabolism, which exhibited a more notable effect in alleviating anemia symptoms, suppressing bone marrow CTLs activation, and improving hematopoietic function in immune-mediated bone marrow failure mouse models. In vitro experiments demonstrated that 3a-M1 directly inhibited CTLs activation and their killing function; the underlying mechanism was at least in part mediated by the selective ferroptosis of overactivated CTLs via the IP<sub>3</sub>R/ORAI pathway. These findings suggest that 3a-M1 represents a novel potential therapeutic agent for AA treatment and ferroptosis may serve as a promising target on CTLs for AA therapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"3 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841037","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：