Pub Date : 2026-02-02DOI: 10.1021/acs.jmedchem.5c03704
Qiangqiang Wei,Ashley J. Taylor,Nagaraju Miriyala,Mahesh A. Barmade,Zachary O. Gentry,Jordan Anderson-Daniels,Kevin B. Teuscher,Mackenzie M. Crow,Chideraa Apakama,Taylor M. South,Tyson A. Rietz,Kangsa Amporndanai,Jason Phan,John L. Sensintaffar,Mark Denison,Taekyu Lee,Stephen W. Fesik
The papain-like protease (PLPro) plays a key role in SARS-CoV-2 replication and represents a promising target for the development of new antiviral therapies. Previous efforts to develop fragment-derived inhibitors of PLPro led to the identification of a novel class of spiro[chromane-2,4′-piperidin]-4-one inhibitors exemplified by lead compound 7. High-resolution covalent cocrystal structures and molecular dynamics simulations were utilized to guide the development of a series of low-nanomolar irreversible PLPro inhibitors, with lead compound 45 demonstrating strong enzymatic inhibition (IC50 = 0.059 μM at T = 60 min) and antiviral activity in A549 cells (EC50 = 2.1 μM at 48 hpi). This novel class of inhibitors represents a promising avenue for the development of therapeutics to overcome the potential of drug-resistant viral strains and future coronavirus outbreaks.
{"title":"Discovery of Spiro[chromane-2,4′-piperidine] Derivatives as Irreversible Inhibitors of SARS-CoV-2 Papain-like Protease","authors":"Qiangqiang Wei,Ashley J. Taylor,Nagaraju Miriyala,Mahesh A. Barmade,Zachary O. Gentry,Jordan Anderson-Daniels,Kevin B. Teuscher,Mackenzie M. Crow,Chideraa Apakama,Taylor M. South,Tyson A. Rietz,Kangsa Amporndanai,Jason Phan,John L. Sensintaffar,Mark Denison,Taekyu Lee,Stephen W. Fesik","doi":"10.1021/acs.jmedchem.5c03704","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03704","url":null,"abstract":"The papain-like protease (PLPro) plays a key role in SARS-CoV-2 replication and represents a promising target for the development of new antiviral therapies. Previous efforts to develop fragment-derived inhibitors of PLPro led to the identification of a novel class of spiro[chromane-2,4′-piperidin]-4-one inhibitors exemplified by lead compound 7. High-resolution covalent cocrystal structures and molecular dynamics simulations were utilized to guide the development of a series of low-nanomolar irreversible PLPro inhibitors, with lead compound 45 demonstrating strong enzymatic inhibition (IC50 = 0.059 μM at T = 60 min) and antiviral activity in A549 cells (EC50 = 2.1 μM at 48 hpi). This novel class of inhibitors represents a promising avenue for the development of therapeutics to overcome the potential of drug-resistant viral strains and future coronavirus outbreaks.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"92 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097901","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 : 2026-02-02DOI: 10.1021/acs.jmedchem.5c03568
Anas Ansari, Radoslaw T. Chrzanowski, Huiying Li, Christine D. Hardy, Amardeep Awasthi, Thomas L. Poulos, Richard B. Silverman
Neuronal nitric oxide synthase (nNOS) is a therapeutic target for the treatment of various neurological disorders and for melanoma. As part of our ongoing efforts to develop potent and selective nNOS inhibitors, we modified our previously reported compound 3 to 4 by introducing an ether linker, leading to a new series of ether-linked 2-aminopyridine-based compounds that exhibit high potency, isoform selectivity, and membrane permeability. Among them, lead compound 4 inhibits human nNOS with a Ki of 25 nM and exhibits 2300-fold selectivity over human endothelial NOS (eNOS) while also displaying high effective permeability in the parallel artificial membrane permeability assay for the blood–brain barrier (PAMPA-BBB) assay (Pe = 16.67 × 10–6 cm/s), indicating favorable blood–brain barrier penetration. Pharmacokinetic evaluation confirmed the brain penetrance of 4 and demonstrated a high oral bioavailability (77%). Moreover, the X-ray crystal structures of representative compounds bound to three NOS isoforms (hnNOS, rnNOS, and heNOS) revealed key binding interactions that contribute to both potency and selectivity.
{"title":"Potent, Selective, and Brain Penetrant Ether-Linked 2-Aminopyridine Inhibitors of Human Neuronal Nitric Oxide Synthase with Excellent Oral Bioavailability","authors":"Anas Ansari, Radoslaw T. Chrzanowski, Huiying Li, Christine D. Hardy, Amardeep Awasthi, Thomas L. Poulos, Richard B. Silverman","doi":"10.1021/acs.jmedchem.5c03568","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03568","url":null,"abstract":"Neuronal nitric oxide synthase (nNOS) is a therapeutic target for the treatment of various neurological disorders and for melanoma. As part of our ongoing efforts to develop potent and selective nNOS inhibitors, we modified our previously reported compound <b>3</b> to <b>4</b> by introducing an ether linker, leading to a new series of ether-linked 2-aminopyridine-based compounds that exhibit high potency, isoform selectivity, and membrane permeability. Among them, lead compound <b>4</b> inhibits human nNOS with a <i>K</i><sub>i</sub> of 25 nM and exhibits 2300-fold selectivity over human endothelial NOS (eNOS) while also displaying high effective permeability in the parallel artificial membrane permeability assay for the blood–brain barrier (PAMPA-BBB) assay (<i>P</i><sub>e</sub> = 16.67 × 10<sup>–6</sup> cm/s), indicating favorable blood–brain barrier penetration. Pharmacokinetic evaluation confirmed the brain penetrance of <b>4</b> and demonstrated a high oral bioavailability (77%). Moreover, the X-ray crystal structures of representative compounds bound to three NOS isoforms (hnNOS, rnNOS, and heNOS) revealed key binding interactions that contribute to both potency and selectivity.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"5 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102042","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}
A systematic evaluation of dppz-based Ru(II), Ir(III), and Re(I) complexes has identified [UDRu] as a potent therapeutic candidate against triple-negative breast cancer stem cells (TNBCSCs). [UDRu] exhibits optimal hydrophilic–lipophilic balance, enabling effective solubility, cellular uptake, and mitochondrial targeting. It induces oxidative stress by depleting GSH and NAD(P)H, promotes ROS generation, disrupts mitochondrial membrane potential, causes DNA damage, and arrests the cell cycle at G2/M. Furthermore, [UDRu] inhibits 3D mammosphere formation and triggers apoptosis through BAX/Bcl-2 regulation and caspase-9 activation. Notably, it also triggers mitophagy through PINK1/Parkin upregulation, offering dual mitochondrial-targeted cytotoxicity. These findings position [UDRu] as a next-generation Ru(II) complex with multitargeted action, holding significant promise for overcoming resistance in TNBC therapy.
{"title":"Turning Off the Powerhouse: Mitochondria-Targeted DPPZ-Ru(II)/Ir(III)/Re(I) Complexes Trigger Dual Mitophagy and Apoptosis To Halt Triple-Negative Breast Cancer","authors":"Utpal Das,Shanooja Shanavas,Shubhangi More,Rishav Das,Pavan Gutti,Meena Jayaprakash,Annamalai Senthil Kumar,Sourav Ghosh,Debasish Mondal,Prasanta Ghosh,Debasish Mishra,Sudheer Shenoy P,Bipasha Bose,Rinku Chakrabarty,Priyankar Paira","doi":"10.1021/acs.jmedchem.5c02210","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02210","url":null,"abstract":"A systematic evaluation of dppz-based Ru(II), Ir(III), and Re(I) complexes has identified [UDRu] as a potent therapeutic candidate against triple-negative breast cancer stem cells (TNBCSCs). [UDRu] exhibits optimal hydrophilic–lipophilic balance, enabling effective solubility, cellular uptake, and mitochondrial targeting. It induces oxidative stress by depleting GSH and NAD(P)H, promotes ROS generation, disrupts mitochondrial membrane potential, causes DNA damage, and arrests the cell cycle at G2/M. Furthermore, [UDRu] inhibits 3D mammosphere formation and triggers apoptosis through BAX/Bcl-2 regulation and caspase-9 activation. Notably, it also triggers mitophagy through PINK1/Parkin upregulation, offering dual mitochondrial-targeted cytotoxicity. These findings position [UDRu] as a next-generation Ru(II) complex with multitargeted action, holding significant promise for overcoming resistance in TNBC therapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"58 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097845","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 : 2026-02-02DOI: 10.1021/acs.jmedchem.5c03222
Mark A. Murcko
Drug discovery is a complex, multiparameter optimization process. I argue that a greater emphasis on optimizing binding affinity will accelerate drug discovery. Note that “optimizing” is not always synonymous with “maximizing”. While affinity is not the only property that matters, the value of optimizing drug–receptor interactions is profound and often underappreciated. Optimizing affinity provides seven distinct benefits: achieving potent tool compounds more quickly; making compounds with increased potency; making more selective compounds; optimizing drug candidates more quickly; encouraging the pursuit of more synthetically challenging compounds; expanding chemical diversity during lead optimization; and minimizing interactions with avoid-ome targets that lead to poor ADME and tox properties. Affinity, alongside other properties, should be viewed as a key strategic component throughout the entire discovery process. A checklist of practical suggestions is offered to enable project teams to more readily achieve the benefits of affinity optimization.
{"title":"The Affinity Advantage","authors":"Mark A. Murcko","doi":"10.1021/acs.jmedchem.5c03222","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03222","url":null,"abstract":"Drug discovery is a complex, multiparameter optimization process. I argue that a greater emphasis on optimizing binding affinity will accelerate drug discovery. Note that “optimizing” is not always synonymous with “maximizing”. While affinity is not the only property that matters, the value of optimizing drug–receptor interactions is profound and often underappreciated. Optimizing affinity provides seven distinct benefits: achieving potent tool compounds more quickly; making compounds with increased potency; making more selective compounds; optimizing drug candidates more quickly; encouraging the pursuit of more synthetically challenging compounds; expanding chemical diversity during lead optimization; and minimizing interactions with avoid-ome targets that lead to poor ADME and tox properties. Affinity, alongside other properties, should be viewed as a key strategic component throughout the entire discovery process. A checklist of practical suggestions is offered to enable project teams to more readily achieve the benefits of affinity optimization.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"80 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097900","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}
Depression is a widespread and increasing mental disorder, yet current antidepressants, including tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), often cause notable side effects and limited efficacy. Hence, safer therapeutic options are needed. Diosgenin, a phytosteroid sapogenin from the Dioscoreaceae plants, has demonstrated therapeutic potential for neurological disorders but is hindered by unclear target mechanism, poor solubility, and limited bioavailability. Here, we synthesized diosgenin derivatives and evaluated their biological activities. Among them, compound 8 exhibited the highest therapeutic index (TI = 19.8), strongly inhibiting LPS-induced NO production with minimal cytotoxicity. Compound 8 suppressed proinflammatory gene expression, showed neuroprotective effects in vitro, ameliorated LPS-induced reactive astrogliosis and microgliosis in vivo, and alleviated LPS-induced depressive-like behaviors in mice. Computational docking and centrifugal ultrafiltration assays identified LY96 as a potential target, suggesting modulation of LPS-TLR4 signaling. Collectively, these findings indicate that compound 8 holds promise as a safer antidepressant candidate.
{"title":"Discovery of a Neuroprotective Diosgenin Derivative as a Novel Antidepressant Candidate Targeting LPS-TLR4 Signaling","authors":"Younghun Yoo,Soo Yeon Baek,Hyelim Lee,Jeehee Lee,Hyowon Lee,Haeun Lee,Hyeonji Ma,Yujin Kim,Hoon-Seong Choi,Jeong Tae Lee,Jae Yeol Lee,Min-Ho Nam,Sanghee Lee,Byungsun Jeon","doi":"10.1021/acs.jmedchem.5c02981","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02981","url":null,"abstract":"Depression is a widespread and increasing mental disorder, yet current antidepressants, including tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), often cause notable side effects and limited efficacy. Hence, safer therapeutic options are needed. Diosgenin, a phytosteroid sapogenin from the Dioscoreaceae plants, has demonstrated therapeutic potential for neurological disorders but is hindered by unclear target mechanism, poor solubility, and limited bioavailability. Here, we synthesized diosgenin derivatives and evaluated their biological activities. Among them, compound 8 exhibited the highest therapeutic index (TI = 19.8), strongly inhibiting LPS-induced NO production with minimal cytotoxicity. Compound 8 suppressed proinflammatory gene expression, showed neuroprotective effects in vitro, ameliorated LPS-induced reactive astrogliosis and microgliosis in vivo, and alleviated LPS-induced depressive-like behaviors in mice. Computational docking and centrifugal ultrafiltration assays identified LY96 as a potential target, suggesting modulation of LPS-TLR4 signaling. Collectively, these findings indicate that compound 8 holds promise as a safer antidepressant candidate.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"91 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097847","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}
Transthyretin (TTR) is a tetrameric protein present in plasma and cerebrospinal fluid that binds to thyroxine (T4) and retinol (vitamin A) to transport them across the blood–retina barrier and to the liver. Mutations on the TTR gene cause destabilization of the tetramer structure leading to misfolded monomers and aggregates, thus triggering several pathologies (i.e., cardiomyopathy and neurodegeneration). The stabilization of TTR tetramer architecture and the silencing of TTR gene expression represent viable therapeutic strategies for amyloidosis. Moreover, the TTR role as a delivery system using drug (bio)conjugates has increasingly been interrogated over the last years to facilitate the transport of different drugs displaying poor pharmacokinetic properties. In this Perspective, we highlight TTR two-faced features as a drug target and carrier, reporting the latest findings in TTR stabilization and its involvement as a drug carrier for the selective drug release on different receptors and cells, thus providing insights for future medicinal chemistry applications.
{"title":"Two Sides of the Same Coin: Transthyretin (TTR) as a Target or Drug Carrier for Drug (Bio)conjugates","authors":"Pasquale Russomanno,Marco Fragai,Margherita Brindisi,Sveva Pelliccia","doi":"10.1021/acs.jmedchem.5c01560","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01560","url":null,"abstract":"Transthyretin (TTR) is a tetrameric protein present in plasma and cerebrospinal fluid that binds to thyroxine (T4) and retinol (vitamin A) to transport them across the blood–retina barrier and to the liver. Mutations on the TTR gene cause destabilization of the tetramer structure leading to misfolded monomers and aggregates, thus triggering several pathologies (i.e., cardiomyopathy and neurodegeneration). The stabilization of TTR tetramer architecture and the silencing of TTR gene expression represent viable therapeutic strategies for amyloidosis. Moreover, the TTR role as a delivery system using drug (bio)conjugates has increasingly been interrogated over the last years to facilitate the transport of different drugs displaying poor pharmacokinetic properties. In this Perspective, we highlight TTR two-faced features as a drug target and carrier, reporting the latest findings in TTR stabilization and its involvement as a drug carrier for the selective drug release on different receptors and cells, thus providing insights for future medicinal chemistry applications.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"25 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097842","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 : 2026-02-02DOI: 10.1021/acs.jmedchem.5c01990
Nicoline N. Jensen,Kristine S. Wilhelmsen,Malene Hall Jensen,Sandrine Mentgen,Francesco Bavo,Uffe Kristiansen,Petrine Wellendorph,Bente Frølund
Extrasynaptic δ-containing γ-aminobutyric acid type A receptors (GABAARs) are potential drug targets in the treatment of several neurological disorders with altered tonic inhibition. Only a few compounds exhibit δ-GABAAR selectivity, among which the imidazo[1,2-a]pyridine compound DS2 constitutes a valuable tool compound. Guided by the recently identified molecular determinants responsible for the positive allosteric modulation by DS2 in the TMD α(+)β(−) interface of the α4β1δ GABAAR, a series of DS2 analogues were synthesized. Replacement of a thienyl moiety with an N-methylated pyrrolyl ring (1e) converted the pharmacological profile from positive to negative allosteric modulation. Compound 1e exhibited no activity at selected γ2-containing GABAAR subtypes, indicating δ-GABAAR selectivity. The ability of 1e to reduce the GABA currents of recombinant receptors carrying α4- and δ-subunit gain-of-function mutations found in patients with neurodevelopmental disorders and epilepsy, as well as being brain-permeable, identifies 1e as a lead compound for reducing pathophysiologically excessive tonic inhibition.
{"title":"Exploring the DS2 Scaffold for GABAA Receptor Modulation: Progress toward the Development of a GABAA δ-Subunit Preferring Negative Allosteric Modulator","authors":"Nicoline N. Jensen,Kristine S. Wilhelmsen,Malene Hall Jensen,Sandrine Mentgen,Francesco Bavo,Uffe Kristiansen,Petrine Wellendorph,Bente Frølund","doi":"10.1021/acs.jmedchem.5c01990","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01990","url":null,"abstract":"Extrasynaptic δ-containing γ-aminobutyric acid type A receptors (GABAARs) are potential drug targets in the treatment of several neurological disorders with altered tonic inhibition. Only a few compounds exhibit δ-GABAAR selectivity, among which the imidazo[1,2-a]pyridine compound DS2 constitutes a valuable tool compound. Guided by the recently identified molecular determinants responsible for the positive allosteric modulation by DS2 in the TMD α(+)β(−) interface of the α4β1δ GABAAR, a series of DS2 analogues were synthesized. Replacement of a thienyl moiety with an N-methylated pyrrolyl ring (1e) converted the pharmacological profile from positive to negative allosteric modulation. Compound 1e exhibited no activity at selected γ2-containing GABAAR subtypes, indicating δ-GABAAR selectivity. The ability of 1e to reduce the GABA currents of recombinant receptors carrying α4- and δ-subunit gain-of-function mutations found in patients with neurodevelopmental disorders and epilepsy, as well as being brain-permeable, identifies 1e as a lead compound for reducing pathophysiologically excessive tonic inhibition.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"3 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097844","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}
E3 ligases are crucial to PROTAC technology, and identifying novel E3 ligase ligands could accelerate the advancement of PROTACs. DCAF11 has shown considerable potential for PROTAC applications. However, the ligands targeting DCAF11 remain limited, highlighting the need for the development of novel ligands for this E3 ligase. In this study, leveraging previous research on DCAF11 ligands, we designed a class of arylidene-thiazoldione scaffolds and applied it to develop PROTACs, resulting in the identification of a potent BRD4 degrader, LGF308. Degradation activity and mechanistic studies demonstrated that the compound LGF308 efficiently induces BRD4 degradation through the proteasomal pathway and via recruitment of DCAF11. This scaffold represents a reliable ligand, capable of facilitating the degradation of various proteins, including CDK4/6, BTK, and FKBP12. Therefore, this study introduces the arylidene-thiazoldione scaffold as a novel DCAF11 ligand and validates its application in PROTAC design, providing strong support for the development of DCAF11-based PROTACs.
{"title":"Arylidene-Thiazoldione Scaffold Acts as the E3 Ligand of DCAF11 for PROTAC Design","authors":"Jinyi Liang,Yuyang Liu,Man Zhao,Lu Chen,Jiajie Qin,Wenjing Ma,Ying Wang,Haiqiang Wu,Ruilin Tian,Tianzi Wei,Lingyin Lao,Jingfei Wang,Hengyu Qu,Hongbo Wang,Rongfang Gao,Sihan Guo,Ming Zhang,Liang Hong,Rui Wang,Guofeng Li","doi":"10.1021/acs.jmedchem.5c02188","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02188","url":null,"abstract":"E3 ligases are crucial to PROTAC technology, and identifying novel E3 ligase ligands could accelerate the advancement of PROTACs. DCAF11 has shown considerable potential for PROTAC applications. However, the ligands targeting DCAF11 remain limited, highlighting the need for the development of novel ligands for this E3 ligase. In this study, leveraging previous research on DCAF11 ligands, we designed a class of arylidene-thiazoldione scaffolds and applied it to develop PROTACs, resulting in the identification of a potent BRD4 degrader, LGF308. Degradation activity and mechanistic studies demonstrated that the compound LGF308 efficiently induces BRD4 degradation through the proteasomal pathway and via recruitment of DCAF11. This scaffold represents a reliable ligand, capable of facilitating the degradation of various proteins, including CDK4/6, BTK, and FKBP12. Therefore, this study introduces the arylidene-thiazoldione scaffold as a novel DCAF11 ligand and validates its application in PROTAC design, providing strong support for the development of DCAF11-based PROTACs.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"80 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097820","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}
Autoimmune diseases remain challenging to treat due to the limitations of TNFα-targeted biologics and the inefficacy of small molecules directly targeting TNFα. RIPK1, a central mediator of TNFα-driven inflammation and necroptosis, offers a promising alternative therapeutic target. Using drug repurposing and phenotype-based high-content screening of 378 clinical-stage kinase inhibitors, TAK-117 (a PI3Kα inhibitor) was identified as a RIPK1 hit compound with a novel pyridoimidazole scaffold. Guided by structure-based optimization and four iterative SAR cycles, WJH-C19 was developed, exhibiting >1000-fold increased RIPK1 potency (IC50 = 5.7 nM) and negligible PI3Kα activity (IC50 > 10 μM). Mechanistically, WJH-C19 suppressed the RIPK1/RIPK3/MLKL signaling axis, attenuating inflammatory responses. Oral administration of WJH-C19 achieved robust efficacy in DSS-induced colitis and CFA-induced arthritis models, with favorable pharmacokinetics and no observable toxicity. These results establish WJH-C19 as a potent lead and highlight the pyridoimidazole scaffold as a privileged chemotype for RIPK1-targeted drug discovery in autoimmune diseases.
{"title":"From Hit to Lead: Discovery of Novel Selective RIPK1 Inhibitor with Pyridoimidazole Scaffold for the Treatment of Autoimmune Diseases through Phenotypic Screening and Structural Optimization","authors":"Jihong Wan,Xiao-Yu Xiong,Zixiang Geng,Benjun Yuan,Youzhen Ma,Yan Zhao,Zhi Ying Dorothy Wong,Xinyi Kang,Rui Fan,Delin Min,Huanren Yan,Yibo Chen,Dong-Yi He,Jian-Ping Zuo,Han-Chen Xu,Yang Ding,Zhiyi Liu,Zixin Hu,Fuzhuo Li,Nannan Sun,Yongfang Zhao,Ze-Min Lin,Mei-Lin Tang","doi":"10.1021/acs.jmedchem.5c03145","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03145","url":null,"abstract":"Autoimmune diseases remain challenging to treat due to the limitations of TNFα-targeted biologics and the inefficacy of small molecules directly targeting TNFα. RIPK1, a central mediator of TNFα-driven inflammation and necroptosis, offers a promising alternative therapeutic target. Using drug repurposing and phenotype-based high-content screening of 378 clinical-stage kinase inhibitors, TAK-117 (a PI3Kα inhibitor) was identified as a RIPK1 hit compound with a novel pyridoimidazole scaffold. Guided by structure-based optimization and four iterative SAR cycles, WJH-C19 was developed, exhibiting >1000-fold increased RIPK1 potency (IC50 = 5.7 nM) and negligible PI3Kα activity (IC50 > 10 μM). Mechanistically, WJH-C19 suppressed the RIPK1/RIPK3/MLKL signaling axis, attenuating inflammatory responses. Oral administration of WJH-C19 achieved robust efficacy in DSS-induced colitis and CFA-induced arthritis models, with favorable pharmacokinetics and no observable toxicity. These results establish WJH-C19 as a potent lead and highlight the pyridoimidazole scaffold as a privileged chemotype for RIPK1-targeted drug discovery in autoimmune diseases.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"23 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097898","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 : 2026-02-02DOI: 10.1021/acs.jmedchem.5c02915
Binbin Yao,Ying Wang,Jinchu Yang,Yuyu Zhang,Bo Liu
Cyclodextrins (CDs) are cyclic oligosaccharides with versatile functions and applications. However, knowledge about their taste properties and underlying molecular mechanisms is still quite limited. In this research, the sweet tastes of α-, β-, and γ-CDs were re-evaluated by a sensory test, and their efficacy to activate the human sweet taste receptor Tas1R2/Tas1R3 was examined with a cell-based assay. The results indicate that CDs are orthodox sweet taste ligands that activate human Tas1R2/Tas1R3. Furthermore, the sweet taste properties of the five derivatives of CDs were also clarified. Moreover, CDs could be classified as a primitive group of sweeteners based on the species-dependent sweet taste. Lastly, it is suggested that the organization of AH, B, and X glucophores in CDs is responsible for their interaction with human Tas1R2/Tas1R3, while the molecular compatibility of the integral configuration is essential for their sweetening power. Our findings provide novel insights for a deeper understanding of the structure–activity relationships of these important biomolecules.
{"title":"Characterization of the Sweet Taste Properties of Cyclodextrins and Their Derivatives and Their Underlying Molecular Mechanisms","authors":"Binbin Yao,Ying Wang,Jinchu Yang,Yuyu Zhang,Bo Liu","doi":"10.1021/acs.jmedchem.5c02915","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02915","url":null,"abstract":"Cyclodextrins (CDs) are cyclic oligosaccharides with versatile functions and applications. However, knowledge about their taste properties and underlying molecular mechanisms is still quite limited. In this research, the sweet tastes of α-, β-, and γ-CDs were re-evaluated by a sensory test, and their efficacy to activate the human sweet taste receptor Tas1R2/Tas1R3 was examined with a cell-based assay. The results indicate that CDs are orthodox sweet taste ligands that activate human Tas1R2/Tas1R3. Furthermore, the sweet taste properties of the five derivatives of CDs were also clarified. Moreover, CDs could be classified as a primitive group of sweeteners based on the species-dependent sweet taste. Lastly, it is suggested that the organization of AH, B, and X glucophores in CDs is responsible for their interaction with human Tas1R2/Tas1R3, while the molecular compatibility of the integral configuration is essential for their sweetening power. Our findings provide novel insights for a deeper understanding of the structure–activity relationships of these important biomolecules.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"42 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097846","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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