Journal of Medicinal Chemistry最新文献

Glycosylation Shapes Isoform-Selective Recognition of Flavonoids by Human Glucose Transporters 糖基化形成人类葡萄糖转运体对黄酮类化合物的异构体选择性识别

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-11-10 DOI: 10.1021/acs.jmedchem.6c00373

Yaru Lu,Anjian Chen,Jiangwen Luo,Fangyin Dai

{"title":"Glycosylation Shapes Isoform-Selective Recognition of Flavonoids by Human Glucose Transporters","authors":"Yaru Lu,Anjian Chen,Jiangwen Luo,Fangyin Dai","doi":"10.1021/acs.jmedchem.6c00373","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c00373","url":null,"abstract":"Human glucose transporters (GLUTs) are pharmacologically relevant membrane proteins interacting with diverse flavonoids, yet previous studies focused largely on individual isoforms and limited ligand sets. Here, we docked 207 flavonoids against all 14 human GLUT isoforms, complemented by microscale thermophoresis (MST) and membrane-embedded molecular dynamics (MD) simulations. Docking revealed heterogeneous interaction profiles associated with differential glycosyl accommodation, distinguishing broad glycosylated flavonoid−preferring (gly-flav−preferring; e.g., GLUT1) and aglycone-biased (agly-flav−biased; e.g., GLUT3) groups. Glycosyl size generally outweighed attachment position, with gly-flav−preferring GLUTs tending to favor larger glycosides and agly-flav−biased GLUTs showing weaker or less favorable responses to glycosyl enlargement. Consistently, MST revealed enhanced GLUT1 binding for selected diglycosides relative to monoglycosides. MD further showed more favorable calculated binding energies for GLUT1 than GLUT3, with size predominating in GLUT1 and position contributing more prominently in GLUT3. Together, these findings highlight glycosylation as a context-dependent determinant of GLUT−flavonoid recognition.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"18 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149374773","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}

引用次数: 0

Unbiased, Target-Agnostic Platform for the Synthesis and Screening of PROTAC Libraries PROTAC文库合成与筛选的无偏、目标不可知平台

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-11-10 DOI: 10.1021/acs.jmedchem.6c02816

Alexander A. Busse,Melanie Rodriguez,Lauren M. Duncan,Anfeng Luo,Juan Diego Bayona,Maheshika S. K. Wanigasekara,Michael M. Rosenblatt,Bruce Posner,Daniel L. Kober,Su Deng,Ping Mu,Uttam K. Tambar

{"title":"Unbiased, Target-Agnostic Platform for the Synthesis and Screening of PROTAC Libraries","authors":"Alexander A. Busse,Melanie Rodriguez,Lauren M. Duncan,Anfeng Luo,Juan Diego Bayona,Maheshika S. K. Wanigasekara,Michael M. Rosenblatt,Bruce Posner,Daniel L. Kober,Su Deng,Ping Mu,Uttam K. Tambar","doi":"10.1021/acs.jmedchem.6c02816","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02816","url":null,"abstract":"Most approaches to PROTAC discovery require prior knowledge of the protein target, limiting the scope of targetable biology. Here we report an unbiased, direct-to-biology platform for the high-throughput synthesis and phenotypic screening of PROTAC libraries. The platform employs the Ugi multicomponent reaction to couple diverse carboxylic acid-containing ligands with VHL-recruiting E3 ligase ligand−linker conjugates in a single well plate step, followed by solid-phase extraction and cell-based phenotypic screening without predetermined target selection. A pilot library derived from seven structurally diverse protein ligands was screened in a cell viability assay against six cancer cell lines, yielding potent and selective hits. Global proteomics identified BRD4 as the primary target of lead compound B5, a BI2536-derived VHL-recruiting degrader that exhibited single-digit nanomolar degradation potency (DC50 = 4.9 nM, Dmax = 96%) and complete selectivity for BRD4 over PLK1. Target engagement and ternary complex formation were confirmed by NanoBRET, Western blot, and Boltz-2 computational modeling. The modularity of the Ugi reaction further enabled direct synthesis of two photoaffinity labeling probes, PALTAC-1 and PALTAC-2, which confirmed BRD4 as a direct binding target via photocrosslinking and pull-down experiments. This platform enables the unbiased discovery of degrader drugs and their targets from phenotypic screens and provides a generalizable framework for converting existing compound libraries into functional PROTAC collections.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"10 3 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149374771","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}

引用次数: 0

Correction to “Two-Step Design of Triazole-Stapled Opioid Agonists Exhibiting Potent and Prolonged Peripheral Analgesic Activity” 更正“三唑类阿片受体激动剂的两步设计，显示出有效和持久的外周镇痛活性”

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-11-09 DOI: 10.1021/acs.jmedchem.6c03343

Mengna Zhang,Jie Gao,Jiamin Feng,Zefei Wang,Xia Wang,Zixiao Wang,Bowen Yu,Yongpeng Liu,Sha Hu,Biao Xu,Ning Li,Feiyun Gao,Quan Fang

引用次数: 0

Broad-Spectrum Antimicrobial Peptide Designed from the Mycobacterium tuberculosis Adenylate Kinase Structure, Inspired by Its LPS/LTA Dual Recognition 从结核分枝杆菌腺苷酸激酶结构设计的广谱抗菌肽，受其LPS/LTA双重识别的启发

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-11-09 DOI: 10.1021/acs.jmedchem.6c02426

Chae Yeong Lee,Hyunjoon Cho,Junho Jeong,Kyusung Chae,Eunha Hwang,Eunhee Kim,Myeong Seon Jeong,Yangmee Kim

{"title":"Broad-Spectrum Antimicrobial Peptide Designed from the Mycobacterium tuberculosis Adenylate Kinase Structure, Inspired by Its LPS/LTA Dual Recognition","authors":"Chae Yeong Lee,Hyunjoon Cho,Junho Jeong,Kyusung Chae,Eunha Hwang,Eunhee Kim,Myeong Seon Jeong,Yangmee Kim","doi":"10.1021/acs.jmedchem.6c02426","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02426","url":null,"abstract":"Broad-spectrum therapeutics targeting multidrug-resistant (MDR) Gram-negative and Gram-positive pathogens remain limited. Utilizing structural insights from Mycobacterium tuberculosis adenylate kinase (MtAdk), which uniquely recognizes both lipopolysaccharide (LPS) and lipoteichoic acid (LTA), we designed broad-spectrum antimicrobial peptides. Through incorporation of non-natural amino acids, terminal acylation, and arginine extension, we developed a lead candidate, YK-mAK-17, with remarkable stability, minimal resistance development, and broad-spectrum activity, particularly against carbapenem-resistant Acinetobacter baumannii (CRAB) and methicillin-resistant Staphylococcus aureus (MRSA). Mechanistic studies revealed an amphipathic α-helix with N-terminal C6 acylation that enhances membrane engagement, driving rapid bactericidal activity via multimodal disruption of membrane integrity and virulence pathways. In septic shock mouse models induced by CRAB and MRSA, YK-mAK-17 significantly improved survival and reduced organ damage. By combining MtAdk-inspired dual LPS/LTA recognition with targeted chemical modifications, YK-mAK-17 represents a promising antimicrobial candidate possessing broad-spectrum antibacterial and anti-inflammatory properties, highlighting the potential of structure-guided peptide design for addressing MDR infections.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"281 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149368386","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}

引用次数: 0

Autonomous Drug Design via Workflow Agents: Integrating Chemical Semantics and Tool-Oriented Automation 基于工作流代理的自主药物设计：集成化学语义和面向工具的自动化

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-11-09 DOI: 10.1021/acs.jmedchem.6c02199

Jingxuan Ge,Youqiao Qian,Hao Luo,Chang-Yu Hsieh,Hui Shi,Jian Wu,Peichen Pan,Yu Kang,Tingjun Hou

{"title":"Autonomous Drug Design via Workflow Agents: Integrating Chemical Semantics and Tool-Oriented Automation","authors":"Jingxuan Ge,Youqiao Qian,Hao Luo,Chang-Yu Hsieh,Hui Shi,Jian Wu,Peichen Pan,Yu Kang,Tingjun Hou","doi":"10.1021/acs.jmedchem.6c02199","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02199","url":null,"abstract":"Large language model (LLM)-based agents have shown promise in automating scientific tasks, yet existing systems for drug discovery often lack strategic, cross-step planning, and multi-objective coordination. Here, we present drugflow-skills, an LLM-driven agent framework that abstracts key drug design operations, including virtual screening, de novo molecule generation, molecular optimization, and multi-target design, into composable and reusable skills. The agent operates under a ReAct paradigm, executing iterative “Thought → Action → Observation” loops while interfacing with the DrugFlow backend. Across five representative tasks targeting ALK, ROS1, and IGF-1R, the agent demonstrates autonomous decision-making, cross-step planning, and multi-objective trade-offs, achieving improved predicted binding scores while reducing predicted toxicity and off-target liabilities. It also provides interpretable rationales and adapts strategies based on human feedback, enabling a human-agent co-optimization loop. These results support dynamic reasoning-driven drug design.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"25 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149368384","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}

引用次数: 0

Discovery of F73, a New Generation RET Inhibitor Overcoming RET Gatekeeper (V804M) and Solvent-Front (G810C/R) Mutations 克服RET Gatekeeper （V804M）和Solvent-Front （G810C/R）突变的新一代RET抑制剂F73的发现

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-11-09 DOI: 10.1021/acs.jmedchem.6c01861

Gangpeng Yang,Xiaowen Niu,Xiaoxu Zhao,Mingjin Xu,Tingyao Li,Li Tan,Haowen Ma,Zhang Zhang,Qian Cai

{"title":"Discovery of F73, a New Generation RET Inhibitor Overcoming RET Gatekeeper (V804M) and Solvent-Front (G810C/R) Mutations","authors":"Gangpeng Yang,Xiaowen Niu,Xiaoxu Zhao,Mingjin Xu,Tingyao Li,Li Tan,Haowen Ma,Zhang Zhang,Qian Cai","doi":"10.1021/acs.jmedchem.6c01861","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01861","url":null,"abstract":"Pharmacological invention of RET offers a compelling strategy to treat patients harboring RET fusions or mutations. Selective RET inhibitors, including pralsetinib and selpercatinib, have demonstrated substantial clinical benefits. However, this efficacy is often compromised by the occurrence of resistance, particularly RET solvent front mutations G810C/R. To address this problem, we performed a systematic structure−activity optimization based on our reported RET inhibitors. Our efforts yielded F73, a next generation RET inhibitor with potent activity against RET mutations including V804M and G810C/R. F73 effectively suppressed RET phosphorylation and downstream SHC activation in Ba/Fa3 cells harboring various RET resistance mutations. Furthermore, it induced apoptosis and cell-cycle arrest in a dose-dependent manner in CCDC6-RET and CCDC6-RET-G810R Ba/F3 cells. Notably, F73 exhibited robust antitumor efficacy in Ba/F3-RET-G810R xenograft models, outperforming selpercatinib, thus supporting its potential to overcome resistance mediated by RET gatekeeper (V804M) and solvent-front (G810C/R) mutations.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"87 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149368388","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}

引用次数: 0

Lipid-Modified CGRP Receptor Antagonists: Balancing Pharmacokinetic Improvement and Potency Loss 脂质修饰的CGRP受体拮抗剂：平衡药代动力学改善和效价损失

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-11-09 DOI: 10.1021/acs.jmedchem.6c02907

Adam L. Schofield,Mária Rožňovcová,Vera D’Aloisio,Ryan K. Y. Tan,Gillian A. Hutcheon,Graeme S. Cottrell,Christopher R. Coxon

{"title":"Lipid-Modified CGRP Receptor Antagonists: Balancing Pharmacokinetic Improvement and Potency Loss","authors":"Adam L. Schofield,Mária Rožňovcová,Vera D’Aloisio,Ryan K. Y. Tan,Gillian A. Hutcheon,Graeme S. Cottrell,Christopher R. Coxon","doi":"10.1021/acs.jmedchem.6c02907","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02907","url":null,"abstract":"Lipidation is a promising strategy for enhancing peptide stability by reducing proteolytic degradation and prolonging systemic exposure. In this study, we systematically evaluated lipid motifs varying in lipid chain length and PEG spacer composition, combined with peptide N-terminal modifications, using a 10-mer calcitonin gene-related peptide receptor antagonist to optimize a candidate for migraine treatment. Incorporation of a C18 diacid lipid motif increased the in vivo (mouse) half-life to 3.5 h. Although lipidation improved serum stability in a size-dependent manner, it was accompanied by a reduction in receptor antagonism, highlighting the balance between pharmacokinetic enhancement and biological activity. These findings improve our understanding of the trade-offs involved in lipidated peptide design and support future optimization strategies. In addition, we developed a rapid, inexpensive, and HPLC-compatible assay for quantifying peptide binding to human serum albumin, overcoming limitations of conventional equilibrium dialysis methods, including non-specific membrane binding, lengthy equilibration times, and peptide degradation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"21 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149368387","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}

引用次数: 0

Design, Synthesis, and Evaluation of a Potent NLRP3 Inflammasome Inhibitor with Favorable Pharmacokinetic and Safety Profiles for Chronic Inflammatory Diseases 一种有效的NLRP3炎性小体抑制剂的设计、合成和评价，具有良好的药代动力学和慢性炎症性疾病的安全性

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-11-07 DOI: 10.1021/acs.jmedchem.6c02821

Haonan Feng,Yichao Kong,Peng Tang,Haoxin Huang,Yutong Li,Wenjing Gu,Yaxia Yuan,Lei Fang,Weiwei Huang,Xiabin Chen,Lei Ma

{"title":"Design, Synthesis, and Evaluation of a Potent NLRP3 Inflammasome Inhibitor with Favorable Pharmacokinetic and Safety Profiles for Chronic Inflammatory Diseases","authors":"Haonan Feng,Yichao Kong,Peng Tang,Haoxin Huang,Yutong Li,Wenjing Gu,Yaxia Yuan,Lei Fang,Weiwei Huang,Xiabin Chen,Lei Ma","doi":"10.1021/acs.jmedchem.6c02821","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02821","url":null,"abstract":"Persistent NLRP3 activation drives chronic inflammatory diseases, necessitating inhibitors with sustained exposure and tolerability. Rational optimization of the hydrophobic and solvent-exposed regions of MCC950 yielded sulfonylurea F34, which inhibited NLRP3-dependent IL-1β release (IC50 = 38.81 nM), with nanomolar potency similar to MCC950, without apparent NLRC4 or AIM2 inhibition. Docking predicted that F34 binds within the MCC950 pocket, where it generally remained during a 200 ns MD simulation. SPR confirmed direct NLRP3 binding (KD = 2.12 μM). In mice, F34 exhibited an oral half-life of 11.89 h and oral bioavailability of 91.36%, potentially contributing to greater efficacy than MCC950 in MSU-induced gouty arthritis and chronic DSS-induced colitis. F34 also showed better tolerability than MCC950 in acute high-dose and 14 day repeated-dose studies, together with weak hERG-channel inhibition (IC50 > 40 μM) and limited CYP inhibition. Thus, optimization preserved nanomolar cellular potency while improving oral exposure, in vivo efficacy, and preliminary tolerability.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"13 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149360383","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}

引用次数: 0

Diverse Computational Strategies Enable the Discovery of p38α−MK2 Molecular Glues 多种计算策略使p38α - MK2分子胶的发现成为可能

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-11-07 DOI: 10.1021/acs.jmedchem.6c01912

Gang Wang,Zef A. Könst,Markus K. Dahlgren,Pooja Arora,Eric Therrien,Sung-Sau So,Pieter H. Bos,Jeffrey A. Bell,Michael A. DiMattia,Eric A. Evangelista,Yefen Zou,Alan S. Futran,Kun Yao,Nicholas A. Boyles,Susanta Haldar,Michael Salmon,Sathesh Bhat,Aleksey I. Gerasyuto,Hideyuki Igawa

{"title":"Diverse Computational Strategies Enable the Discovery of p38α−MK2 Molecular Glues","authors":"Gang Wang,Zef A. Könst,Markus K. Dahlgren,Pooja Arora,Eric Therrien,Sung-Sau So,Pieter H. Bos,Jeffrey A. Bell,Michael A. DiMattia,Eric A. Evangelista,Yefen Zou,Alan S. Futran,Kun Yao,Nicholas A. Boyles,Susanta Haldar,Michael Salmon,Sathesh Bhat,Aleksey I. Gerasyuto,Hideyuki Igawa","doi":"10.1021/acs.jmedchem.6c01912","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01912","url":null,"abstract":"Mitogen-activated protein kinase-activated protein kinase 2 (MK2) phosphorylates AU-rich element-binding proteins (AUBPs) that modulate the stability of cytokine mRNA. An emerging class of inhibitors creates a ternary complex between upstream kinase p38α and MK2. These molecular glues demonstrate sustained efficacy relative to orthosteric inhibitors of either p38α or MK2; however, their mechanism of action presents challenges to computationally driven design. Herein we describe in silico hit identification strategies leveraging free energy perturbation coupled with machine learning to triage and prioritize ligands from diverse chemical sources and identify multiple structurally diverse, potent, and highly selective p38α−MK2 molecular glues. Lead compounds 14 and 28 demonstrated an attractive PK profile with sufficient coverage of human whole blood EC50 and displayed pronounced reduction of TNFα levels after PO dosing in lipopolysaccharide mouse models, illustrating the value of our in silico hit identification strategies and optimization of non-degrading molecular glues.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"6 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149360382","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}

引用次数: 0

Potent and Selective Caspase-2 Inhibitors: Biological Profiling, Structural Characterization, and Challenges of Molecular Instability 强效和选择性Caspase-2抑制剂：生物学分析、结构表征和分子不稳定性的挑战

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-11-07 DOI: 10.1021/acs.jmedchem.6c01370

Lisa Forster,Bernadette Vallaster,Alexander Hubmann,Merlin Bresinsky,Jessica L. Fuller,Ke Shi,Ian P. Lapcinski,Peng Liu,Mu Yang,Jessica M. Strasser,Kathryn M. Nelson,Kristen John,Deepti Mudaliar,Lukas Wirth,Jonas Daschner,Herwig Pongratz,Karen H. Ashe,Michael A. Walters,Steffen Pockes

{"title":"Potent and Selective Caspase-2 Inhibitors: Biological Profiling, Structural Characterization, and Challenges of Molecular Instability","authors":"Lisa Forster,Bernadette Vallaster,Alexander Hubmann,Merlin Bresinsky,Jessica L. Fuller,Ke Shi,Ian P. Lapcinski,Peng Liu,Mu Yang,Jessica M. Strasser,Kathryn M. Nelson,Kristen John,Deepti Mudaliar,Lukas Wirth,Jonas Daschner,Herwig Pongratz,Karen H. Ashe,Michael A. Walters,Steffen Pockes","doi":"10.1021/acs.jmedchem.6c01370","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01370","url":null,"abstract":"Caspase-2 (Casp2) has emerged as a promising therapeutic target for neurodegenerative diseases due to its role in pathological tau processing. Here, we designed and synthesized a series of 48 novel peptidomimetic Casp2 inhibitors organized into distinct structural classes. Compounds were evaluated for Casp2 inhibition and selectivity against Casp1, 3, 4, 5, 6, 7, 8, 9, and 10. Inhibitors Idc(hE)G(Dab)D-CHO (32) and Idc(hE)G((S)-Me-THIQ)D-CHO (33) exhibited low nanomolar potency and ≥537-fold selectivity over Casp3. These unprecedented scaffold modifications are consistent with preferred steric arrangements between the P2 and P3 positions. Biochemical assays demonstrated the blockade of tau truncation and impaired the formation of toxic Δtau314. High-resolution crystal structures of compounds 2 and 33 bound to Casp2 revealed binding interactions consistent with the observed SAR. Although Idc(hE)V((S)-Me-THIQ)D-CHO (3, MUR-65) showed favorable ADME and pharmacokinetic properties, limited membrane permeability, insufficient blood−brain barrier penetration, and P5 indoline instability remain key challenges for further development.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"15 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149360384","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}

引用次数: 0