Pub Date : 2026-02-01DOI: 10.1021/acs.jmedchem.5c02390
Naiera M. Helmy,Dorna Davani-Davari,Keykavous Parang
Antimicrobial resistance poses a growing global health threat, necessitating the development of new therapeutic strategies. Antimicrobial peptides (AMPs) are promising candidates due to their broad-spectrum activity and multitarget mechanisms; however, their clinical translation is limited by a short in vivo half-life, susceptibility to proteolysis, cytotoxicity, and suboptimal pharmacokinetics. Fatty acid conjugation (lipidation) has emerged as an effective modification strategy to overcome these challenges by enhancing membrane interactions, antimicrobial potency, proteolytic stability, and in vivo persistence, often through binding to serum albumin. In this Perspective, we examine common lipidation approaches, including N-terminal acylation and side-chain modification, and their effects on AMP selectivity, spectrum of activity, and stability. We also highlight emerging applications of fatty-acid-conjugated AMPs in drug delivery, antibiofilm therapies, and the treatment of resistant pathogens. Finally, we discuss key safety considerations and outline future directions, including lipid optimization and AI-guided design of next-generation antimicrobial agents.
{"title":"Fatty Acid-Conjugated Antimicrobial Peptides: Advances in Design, Activity, and Therapeutic Potential","authors":"Naiera M. Helmy,Dorna Davani-Davari,Keykavous Parang","doi":"10.1021/acs.jmedchem.5c02390","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02390","url":null,"abstract":"Antimicrobial resistance poses a growing global health threat, necessitating the development of new therapeutic strategies. Antimicrobial peptides (AMPs) are promising candidates due to their broad-spectrum activity and multitarget mechanisms; however, their clinical translation is limited by a short in vivo half-life, susceptibility to proteolysis, cytotoxicity, and suboptimal pharmacokinetics. Fatty acid conjugation (lipidation) has emerged as an effective modification strategy to overcome these challenges by enhancing membrane interactions, antimicrobial potency, proteolytic stability, and in vivo persistence, often through binding to serum albumin. In this Perspective, we examine common lipidation approaches, including N-terminal acylation and side-chain modification, and their effects on AMP selectivity, spectrum of activity, and stability. We also highlight emerging applications of fatty-acid-conjugated AMPs in drug delivery, antibiofilm therapies, and the treatment of resistant pathogens. Finally, we discuss key safety considerations and outline future directions, including lipid optimization and AI-guided design of next-generation antimicrobial agents.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097905","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 : 2026-01-31DOI: 10.1021/acs.jmedchem.5c03342
Skye B Brettell,Carla Fuentes-Guerra Bustos,Saumya Sharma,Gillian Cann,Lauren V Carruthers,Abbey Begen,Graeme Milligan,David J Clarke,Andrew B Tobin,Andrew G Jamieson
The emergence ofPlasmodium falciparumresistance to frontline therapies highlights the urgent need for new antimalarial agents. The essential, multistage kinase PfCLK3 is a validated target, and covalent kinase inhibitors (CKIs) offer potential for durable inhibition. However, CKI design has largely prioritised warhead reactivity over the geometric requirements which govern covalent bond formation. Herein, we describe a geometry-first approach to optimize covalent PfCLK3 inhibitors, starting from the highly reactive chloroacetamide SB4-17 (2). Systematic variation of warhead and linker geometry revealed that maintaining the α-reactive geometry of the chloroacetamide scaffold enables covalent engagement of Cys368 with substantially less reactive electrophiles. Notably, the methyl sulfamate analogue SB5-171 (14) showed potent antiparasitic activity (EC50 = 104 nM) and improved metabolic stability (t1/2 = 35 min in mouse hepatocytes). These findings demonstrate that geometric optimization can decouple covalent engagement from high intrinsic reactivity, providing a rational framework for designing selective, drug-like CKIs.
{"title":"Shaping Antimalarials: A Geometry-First Approach to PfCLK3 Covalent Inhibitors.","authors":"Skye B Brettell,Carla Fuentes-Guerra Bustos,Saumya Sharma,Gillian Cann,Lauren V Carruthers,Abbey Begen,Graeme Milligan,David J Clarke,Andrew B Tobin,Andrew G Jamieson","doi":"10.1021/acs.jmedchem.5c03342","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03342","url":null,"abstract":"The emergence ofPlasmodium falciparumresistance to frontline therapies highlights the urgent need for new antimalarial agents. The essential, multistage kinase PfCLK3 is a validated target, and covalent kinase inhibitors (CKIs) offer potential for durable inhibition. However, CKI design has largely prioritised warhead reactivity over the geometric requirements which govern covalent bond formation. Herein, we describe a geometry-first approach to optimize covalent PfCLK3 inhibitors, starting from the highly reactive chloroacetamide SB4-17 (2). Systematic variation of warhead and linker geometry revealed that maintaining the α-reactive geometry of the chloroacetamide scaffold enables covalent engagement of Cys368 with substantially less reactive electrophiles. Notably, the methyl sulfamate analogue SB5-171 (14) showed potent antiparasitic activity (EC50 = 104 nM) and improved metabolic stability (t1/2 = 35 min in mouse hepatocytes). These findings demonstrate that geometric optimization can decouple covalent engagement from high intrinsic reactivity, providing a rational framework for designing selective, drug-like CKIs.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"93 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089090","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}
Intraoperative nerve injury remains a major surgical challenge. Rapid, wash-free nerve visualization is highly desirable for fluorescence image-guided surgery (FIGS), yet existing probes lack spray compatibility and sufficient fluorogenicity. Here we introduce N4, a near-infrared fluorogenic spray probe that enables ∼10 s, wash-free visualization of peripheral nerves. N4 is engineered to remain nonfluorescent in its spirocyclic form under physiological conditions but undergoes MBP-triggered spiro-opening to a bright zwitterionic state, yielding a 6.3-fold turn-on. Topical spraying of N4 produces clear sciatic and vagus nerve imaging with nerve-to-muscle contrast up to 6.4 and allows visualization of branches as small as 0.12 mm, even under blood-contaminated fields. N4 provides a robust platform for real-time FIGS nerve mapping and advances the development of next-generation fluorogenic surgical probes.
{"title":"A Near-Infrared Fluorogenic Spray Probe for Rapid and Wash-Free Intraoperative Nerve Imaging.","authors":"Lijun Wang,Yushu Xi,Pingting Gao,Cheng Ma,Wanxin Bao,Lei Song,Quanlin Li,Xingdang Liu,Pinghong Zhou,Lin Yuan,Lu Wang","doi":"10.1021/acs.jmedchem.5c03089","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03089","url":null,"abstract":"Intraoperative nerve injury remains a major surgical challenge. Rapid, wash-free nerve visualization is highly desirable for fluorescence image-guided surgery (FIGS), yet existing probes lack spray compatibility and sufficient fluorogenicity. Here we introduce N4, a near-infrared fluorogenic spray probe that enables ∼10 s, wash-free visualization of peripheral nerves. N4 is engineered to remain nonfluorescent in its spirocyclic form under physiological conditions but undergoes MBP-triggered spiro-opening to a bright zwitterionic state, yielding a 6.3-fold turn-on. Topical spraying of N4 produces clear sciatic and vagus nerve imaging with nerve-to-muscle contrast up to 6.4 and allows visualization of branches as small as 0.12 mm, even under blood-contaminated fields. N4 provides a robust platform for real-time FIGS nerve mapping and advances the development of next-generation fluorogenic surgical probes.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"17 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089006","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 : 2026-01-30DOI: 10.1021/acs.jmedchem.5c02154
Amardeep Awasthi,Anika Patel,Huiying Li,Koon Mook Kang,Christine D Hardy,Anas Ansari,Raghad Nowar,Md Emtiaz Hasan,Sun Yang,Thomas L Poulos,Richard B Silverman
In 2024, an estimated 100,640 new cases of invasive melanoma were diagnosed in the U.S., with 9290 deaths. Our previous studies revealed that neuronal nitric oxide synthase (nNOS) derived nitric oxide plays a critical role in melanoma progression, making nNOS inhibition a promising strategy. High structural similarity among NOS isoforms requires careful design of nNOS inhibitors to avoid off-target effects. Our previous lead, HH044, demonstrated potent antimelanoma activity but exhibited only moderate nNOS selectivity. Here, we utilized a structure-based approach to design nNOS inhibitors that promote interactions with human nNOS-specific residue His342. Compound 9 exhibited inhibition of both human (Ki = 1.7 nM) and rat nNOS (Ki = 2.3 nM), with 5654-fold selectivity over human eNOS and 250-fold selectivity over iNOS. X-ray crystallography and molecular modeling revealed a novel SAR, forming the basis for nNOS inhibition and providing a foundation for further innovative design of nNOS inhibitors for melanoma treatment.
{"title":"New Inhibitors of Neuronal Nitric Oxide Synthase for the Treatment of Melanoma.","authors":"Amardeep Awasthi,Anika Patel,Huiying Li,Koon Mook Kang,Christine D Hardy,Anas Ansari,Raghad Nowar,Md Emtiaz Hasan,Sun Yang,Thomas L Poulos,Richard B Silverman","doi":"10.1021/acs.jmedchem.5c02154","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02154","url":null,"abstract":"In 2024, an estimated 100,640 new cases of invasive melanoma were diagnosed in the U.S., with 9290 deaths. Our previous studies revealed that neuronal nitric oxide synthase (nNOS) derived nitric oxide plays a critical role in melanoma progression, making nNOS inhibition a promising strategy. High structural similarity among NOS isoforms requires careful design of nNOS inhibitors to avoid off-target effects. Our previous lead, HH044, demonstrated potent antimelanoma activity but exhibited only moderate nNOS selectivity. Here, we utilized a structure-based approach to design nNOS inhibitors that promote interactions with human nNOS-specific residue His342. Compound 9 exhibited inhibition of both human (Ki = 1.7 nM) and rat nNOS (Ki = 2.3 nM), with 5654-fold selectivity over human eNOS and 250-fold selectivity over iNOS. X-ray crystallography and molecular modeling revealed a novel SAR, forming the basis for nNOS inhibition and providing a foundation for further innovative design of nNOS inhibitors for melanoma treatment.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"282 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089007","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}
Successful compound optimization heavily relies on medicinal chemist expertise. In this work, we curated nearly 9000 molecular optimization strategies from the medicinal chemistry literature. Driven by expert knowledge, we constructed the MolOpt framework based on graph deep learning to expand these structural optimization strategies. Leveraging both expert-derived strategies and MolOpt, we developed AutoOptimizer, an automatic platform used for molecular optimization. To demonstrate the platform's practical application, we conducted case studies on fibroblast growth factor receptor 4 (FGFR4) and hematopoietic progenitor kinase 1 (HPK1). Experimental validation identified M8 and M9, which exhibited IC50 values of 17.6 and 46.5 nM against FGFR4 and HPK1, respectively, representing a 77.6-fold and 51.6-fold improvement over starting molecules. To our knowledge, this represents the first deep learning-generated molecular optimization strategy database grounded in the expertise of medicinal chemists. We anticipate that AutoOptimizer will provide valuable insights and accelerate lead optimization, thereby advancing drug discovery efforts.
{"title":"Integrating Medicinal Chemist Expertise with Deep Learning for Automated Molecular Optimization.","authors":"Li Liang,Xinyi Yang,Boheng Wan,Lingxi Gu,Yan Yang,Wuchen Xie,Xiaowen Dai,Yuan Xu,Xian Wei,Haichun Liu,Tao Lu,Yadong Chen,Yanmin Zhang","doi":"10.1021/acs.jmedchem.5c03746","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03746","url":null,"abstract":"Successful compound optimization heavily relies on medicinal chemist expertise. In this work, we curated nearly 9000 molecular optimization strategies from the medicinal chemistry literature. Driven by expert knowledge, we constructed the MolOpt framework based on graph deep learning to expand these structural optimization strategies. Leveraging both expert-derived strategies and MolOpt, we developed AutoOptimizer, an automatic platform used for molecular optimization. To demonstrate the platform's practical application, we conducted case studies on fibroblast growth factor receptor 4 (FGFR4) and hematopoietic progenitor kinase 1 (HPK1). Experimental validation identified M8 and M9, which exhibited IC50 values of 17.6 and 46.5 nM against FGFR4 and HPK1, respectively, representing a 77.6-fold and 51.6-fold improvement over starting molecules. To our knowledge, this represents the first deep learning-generated molecular optimization strategy database grounded in the expertise of medicinal chemists. We anticipate that AutoOptimizer will provide valuable insights and accelerate lead optimization, thereby advancing drug discovery efforts.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"82 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089112","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 : 2026-01-30DOI: 10.1021/acs.jmedchem.5c03494
Johannes Karges
Reactive oxygen species (ROS) are highly reactive molecules derived from molecular oxygen that play critical roles in cellular signaling, homeostasis, and the regulation of various physiological and pathological processes. Accurate detection and quantification of ROS are essential for elucidating their roles in health and disease. Despite significant advances in ROS probe development, challenges persist due to their short lifetimes, high reactivity, and their chemical diversity. This perspective article provides a critical evaluation of the limitations of the most commonly applied probe molecule DCFH-DA. Capitalizing on this, recommendations with practical applications in the lab for the specific detection of hydrogen peroxide, hydroxyl radical, singlet oxygen, superoxide anion, and peroxynitrite are provided. By integrating current knowledge on ROS probe technologies, this work aims to guide researchers in reliably assessing ROS in complex biological systems, thereby facilitating a deeper understanding of ROS-mediated processes and their implications for disease research and therapeutic development.
{"title":"Reactive Oxygen Species Detection with Fluorescent Probes: Limitations and Recommendations beyond DCFH-DA.","authors":"Johannes Karges","doi":"10.1021/acs.jmedchem.5c03494","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03494","url":null,"abstract":"Reactive oxygen species (ROS) are highly reactive molecules derived from molecular oxygen that play critical roles in cellular signaling, homeostasis, and the regulation of various physiological and pathological processes. Accurate detection and quantification of ROS are essential for elucidating their roles in health and disease. Despite significant advances in ROS probe development, challenges persist due to their short lifetimes, high reactivity, and their chemical diversity. This perspective article provides a critical evaluation of the limitations of the most commonly applied probe molecule DCFH-DA. Capitalizing on this, recommendations with practical applications in the lab for the specific detection of hydrogen peroxide, hydroxyl radical, singlet oxygen, superoxide anion, and peroxynitrite are provided. By integrating current knowledge on ROS probe technologies, this work aims to guide researchers in reliably assessing ROS in complex biological systems, thereby facilitating a deeper understanding of ROS-mediated processes and their implications for disease research and therapeutic development.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"93 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146088890","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}
Phosphodiesterase-4 (PDE4) inhibitors show potential for treating ischemic stroke, but are often constrained by emesis or low blood-brain barrier (BBB) permeability. To overcome these challenges, this paper developed novel PDE4 inhibitors via AI-driven structural evolution of natural antistroke products and identified the Phthalide derivative B05 as a PDE4 inhibitor exhibiting excellent selectivity (selectivity index > 420), favorable pharmacological properties (F = 15.5%), and good BBB permeability. Significantly, B05 did not induce vomiting at ultrahigh doses (60 mg/kg), a significant advantage over conventional PDE4 inhibitors. B05 protected neuronal cells from oxygen-glucose deprivation and reoxygenation-induced injury. Additionally, in the middle cerebral artery occlusion and reperfusion model, B05 significantly reduced infarct volume, preserved BBB integrity, attenuated cerebral edema, inhibited astrocyte and microglial activation, prevented ischemia-induced neuronal apoptosis, and improved poststroke motor function and cognitive performance. These findings support the potential of B05 as a promising candidate for the treatment of ischemic stroke.
{"title":"Discovery of Novel Natural Product-Based PDE4 Inhibitors for Ischemic Stroke Treatment without Emetogenicity at Ultra-High Doses.","authors":"Chuang Xia,Mingjia Yu,Yujie Ni,Shanfang Fang,Kaiwen Feng,Tingting Zhang,Chunping Gu,Kaibin Huang,Zhong-Zhen Zhou","doi":"10.1021/acs.jmedchem.5c02951","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02951","url":null,"abstract":"Phosphodiesterase-4 (PDE4) inhibitors show potential for treating ischemic stroke, but are often constrained by emesis or low blood-brain barrier (BBB) permeability. To overcome these challenges, this paper developed novel PDE4 inhibitors via AI-driven structural evolution of natural antistroke products and identified the Phthalide derivative B05 as a PDE4 inhibitor exhibiting excellent selectivity (selectivity index > 420), favorable pharmacological properties (F = 15.5%), and good BBB permeability. Significantly, B05 did not induce vomiting at ultrahigh doses (60 mg/kg), a significant advantage over conventional PDE4 inhibitors. B05 protected neuronal cells from oxygen-glucose deprivation and reoxygenation-induced injury. Additionally, in the middle cerebral artery occlusion and reperfusion model, B05 significantly reduced infarct volume, preserved BBB integrity, attenuated cerebral edema, inhibited astrocyte and microglial activation, prevented ischemia-induced neuronal apoptosis, and improved poststroke motor function and cognitive performance. These findings support the potential of B05 as a promising candidate for the treatment of ischemic stroke.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"66 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146088892","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 : 2026-01-30DOI: 10.1021/acs.jmedchem.5c02855
Jing You,Lu Yang,Yaru Qin,Chenyu Tian,Xin Yang,Mingli Xiang,Linli Li,Shengyong Yang
Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, contributes to diverse pathological conditions. However, the clinical translation of ferroptosis inhibitors has been hampered by the limited efficacy or suboptimal pharmacokinetic profiles. Here, we report the discovery of diazepine derivatives as a new structural class of ferroptosis inhibitors. Through systematic structure-activity relationship optimization, we identified YL3147 as the most potent analogue, demonstrating exceptional cellular potency with an EC50 of 0.8 nM. Mechanistically, YL3147 functions as a radical-trapping antioxidant, directly halting the propagation of lipid peroxidation and thereby blocking ferroptosis. This compound also exhibits favorable drug-like pharmacokinetic properties. In vivo, YL3147 provided substantial protection against doxorubicin-induced cardiomyopathy in both acute and chronic murine models, with no detectable toxicity. Together, these findings establish YL3147 as a promising lead compound for the treatment of ferroptosis-related diseases, warranting further preclinical development.
{"title":"Discovery and Structure-Activity Relationship Studies of Diazepine Derivatives as a New Class of Ferroptosis Inhibitors with Potent Efficacy in the Doxorubicin-Induced Cardiomyopathy Model.","authors":"Jing You,Lu Yang,Yaru Qin,Chenyu Tian,Xin Yang,Mingli Xiang,Linli Li,Shengyong Yang","doi":"10.1021/acs.jmedchem.5c02855","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02855","url":null,"abstract":"Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, contributes to diverse pathological conditions. However, the clinical translation of ferroptosis inhibitors has been hampered by the limited efficacy or suboptimal pharmacokinetic profiles. Here, we report the discovery of diazepine derivatives as a new structural class of ferroptosis inhibitors. Through systematic structure-activity relationship optimization, we identified YL3147 as the most potent analogue, demonstrating exceptional cellular potency with an EC50 of 0.8 nM. Mechanistically, YL3147 functions as a radical-trapping antioxidant, directly halting the propagation of lipid peroxidation and thereby blocking ferroptosis. This compound also exhibits favorable drug-like pharmacokinetic properties. In vivo, YL3147 provided substantial protection against doxorubicin-induced cardiomyopathy in both acute and chronic murine models, with no detectable toxicity. Together, these findings establish YL3147 as a promising lead compound for the treatment of ferroptosis-related diseases, warranting further preclinical development.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"22 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089008","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 : 2026-01-30DOI: 10.1021/acs.jmedchem.5c02785
Gang Liu,Shuaishuai Liu,Sangwoo Cho,Hee-Don Chae,Wei Zhou,Lingtian Zhang,Avinash Khanna,Xin Zeng,Xinlin Du,Hugh Zhu,Tzu-Pei Chang,Nathan Max,Megha Kumar,Cynthia Chen,Lance Lee
Bruton's tyrosine kinase (BTK) represents a key therapeutic target for B-cell malignancies. While covalent inhibitors have shown efficacy, the emergence of resistant BTK mutants necessitates the development of noncovalent alternatives with improved selectivity and tolerability profiles. Utilizing structure-based drug design, we identified HBC-12551, a novel noncovalent BTK inhibitor. By strategically incorporating a hydrogen-bonding interaction with the backbone NH of Cys481, HBC-12551 demonstrated significantly enhanced potency. This compound potently inhibited both wild-type and C481S mutant BTK and exhibited robust antiproliferative effects in B-cell lymphoma cell lines. Preclinical studies further revealed promising antitumor activity in vivo, coupled with favorable pharmacokinetic properties. These findings suggest that HBC-12551 holds significant potential as a promising therapeutic candidate for the treatment of B-cell malignancies.
{"title":"Strategic Use of Benzylic Alcohols Reveals Cryptic Hydrogen-Bonding Interactions: Discovery of HBC-12551 as a Potent Noncovalent Bruton's Tyrosine Kinase Inhibitor.","authors":"Gang Liu,Shuaishuai Liu,Sangwoo Cho,Hee-Don Chae,Wei Zhou,Lingtian Zhang,Avinash Khanna,Xin Zeng,Xinlin Du,Hugh Zhu,Tzu-Pei Chang,Nathan Max,Megha Kumar,Cynthia Chen,Lance Lee","doi":"10.1021/acs.jmedchem.5c02785","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02785","url":null,"abstract":"Bruton's tyrosine kinase (BTK) represents a key therapeutic target for B-cell malignancies. While covalent inhibitors have shown efficacy, the emergence of resistant BTK mutants necessitates the development of noncovalent alternatives with improved selectivity and tolerability profiles. Utilizing structure-based drug design, we identified HBC-12551, a novel noncovalent BTK inhibitor. By strategically incorporating a hydrogen-bonding interaction with the backbone NH of Cys481, HBC-12551 demonstrated significantly enhanced potency. This compound potently inhibited both wild-type and C481S mutant BTK and exhibited robust antiproliferative effects in B-cell lymphoma cell lines. Preclinical studies further revealed promising antitumor activity in vivo, coupled with favorable pharmacokinetic properties. These findings suggest that HBC-12551 holds significant potential as a promising therapeutic candidate for the treatment of B-cell malignancies.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"81 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089113","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}
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