NPJ drug discovery最新文献

Physicochemical rule-embedded generative modeling for constrained peptide therapeutics. 约束肽治疗的物理化学规则嵌入生成模型。

NPJ drug discovery Pub Date : 2026-10-29 DOI: 10.1038/s44386-026-00090-1

Yuzhou Wang, Dongsheng Cao, Xiangzheng Fu, Xiangxiang Zeng, Xiaojun Yao

引用次数: 0

Design of Tissue-Selective PROTACs Through Recruiting E3 Ligase Scaffolding Protein MAGEA11. 通过招募E3连接酶支架蛋白MAGEA11设计组织选择性PROTACs。

NPJ drug discovery Pub Date : 2026-10-26 DOI: 10.1038/s44386-026-00081-2

Isabella E Jacobsen, Rui Shi, Cole R Scholtz, William C K Pomerantz, Gunda I Georg

{"title":"Design of Tissue-Selective PROTACs Through Recruiting E3 Ligase Scaffolding Protein MAGEA11.","authors":"Isabella E Jacobsen, Rui Shi, Cole R Scholtz, William C K Pomerantz, Gunda I Georg","doi":"10.1038/s44386-026-00081-2","DOIUrl":"10.1038/s44386-026-00081-2","url":null,"abstract":"Proteolysis targeting chimeras (PROTACs) are an emerging therapeutic modality that induces protein degradation by recruiting E3 ligases. Most reported PROTACs recruit ubiquitously expressed E3 ligases, such as cereblon and the von Hippel-Lindau tumor suppressor. Of the additional 600 + E3 ligases, recruiting those with tissue-restricted expression is attractive for increasing the specificity of PROTACs. This work describes the first reported PROTAC that recruits the tissue-specific E3 ligase scaffolding protein MAGEA11. As an initial demonstration, bromodomain and extra-terminal domain (BET)-targeting PROTACs that recruit MAGEA11 were synthesized and screened in osteosarcoma U2OS cells, identifying lead compound 105B. 105B degrades BET proteins in U2OS cells (BRD4 DC₅₀ = 0.130 nM, Dmax = 78%) and KYSE180 esophageal squamous cell carcinoma cell lines (DC₅₀ = 40 nM, Dmax = 70%), but shows no degradation in non-cancerous HEK293T cells. Mechanistic studies confirmed 105B's dependence on the ubiquitin-proteasome system and MAGEA11 and HUWE1 expression. 105B decreased levels of BET-regulated gene products RUNX2 and KRT14; however, improvements are still necessary to affect selective cytotoxicity. This work reports the first example of a PROTAC that recruits a tissue-specific E3 ligase to enable cancer-restricted degradation of BET proteins and highlights the need for further development of MAGEA11-recruiting degraders.","PeriodicalId":520448,"journal":{"name":"NPJ drug discovery","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13710757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149280591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Molecular glue mediated degradation of cannabinoid receptor 1 for cancer therapy. 分子胶介导的大麻素受体1降解用于癌症治疗。

NPJ drug discovery Pub Date : 2026-10-26 DOI: 10.1038/s44386-026-00087-w

Aseel Kashkush, Kisanet Tadesse, Binyamin Insler, Raphael I Benhamou

{"title":"Molecular glue mediated degradation of cannabinoid receptor 1 for cancer therapy.","authors":"Aseel Kashkush, Kisanet Tadesse, Binyamin Insler, Raphael I Benhamou","doi":"10.1038/s44386-026-00087-w","DOIUrl":"10.1038/s44386-026-00087-w","url":null,"abstract":"The cannabinoid receptor type 1 (CB1R), a G protein-coupled receptor within the endocannabinoid system, has been implicated in oncogenic signaling and cancer progression. Here, we developed a series of compact covalent molecular glue degraders designed to reduce CB1R abundance by recruiting components of the ubiquitin-proteasome system. Using rimonabant as a CB1R-binding scaffold, we generated small molecules incorporating electrophilic E3 ligase-recruiting handles and identified MG-CB2 as the most active degrader. MG-CB2 induced concentration- and time-dependent depletion of CB1R in MCF-7 breast cancer and HepG2 hepatocellular carcinoma cells. Proteasome inhibition blocked MG-CB2-mediated CB1R loss, while RNF126 knockdown abrogated degradation, supporting a proteasome- and RNF126-dependent mechanism. Rimonabant competition and cellular thermal shift experiments further supported cellular engagement of CB1R by MG-CB2. CB1R degradation was accompanied by modulation of CB1R-associated signaling, including reduced phosphorylation of ERK and mTOR and decreased BCL2 expression, along with reduced cancer-cell viability and migration. These findings establish covalent molecular glue-mediated degradation as a strategy for modulating CB1R abundance and signaling and expand the application of targeted protein degradation to a transmembrane GPCR.","PeriodicalId":520448,"journal":{"name":"NPJ drug discovery","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13710980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149280549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Activity-based proteomics discovery of deubiquitinating enzyme inhibitors with immunomodulatory activity. 基于活性的蛋白质组学发现具有免疫调节活性的去泛素化酶抑制剂。

NPJ drug discovery Pub Date : 2026-10-26 DOI: 10.1038/s44386-026-00092-z

Hannah B L Jones, Simeon D Draganov, Sofia Schönbauer Huamán, Peter A C Wing, Chuong Nguyen, Zhu Liang, Julia Dörner, Jasper Lithgow, Emma Murphy, Alice Beard, Angela Chen, Andrea Pierangelini, Jack W Houghton, Mackenzie E Robert, Sarah Flannery, Cara J Ellison, Sakshi Sharma, Anthony Tumber, Lynn Wambua, Iolanda Vendrell, Edward W Tate, Paul R Elliott, Graham M West, Darragh P O'Brien, Eidarus Salah, Andrew P Turnbull, Christopher J Schofield, Benedikt M Kessler, Lennart Brewitz, Adán Pinto-Fernández

{"title":"Activity-based proteomics discovery of deubiquitinating enzyme inhibitors with immunomodulatory activity.","authors":"Hannah B L Jones, Simeon D Draganov, Sofia Schönbauer Huamán, Peter A C Wing, Chuong Nguyen, Zhu Liang, Julia Dörner, Jasper Lithgow, Emma Murphy, Alice Beard, Angela Chen, Andrea Pierangelini, Jack W Houghton, Mackenzie E Robert, Sarah Flannery, Cara J Ellison, Sakshi Sharma, Anthony Tumber, Lynn Wambua, Iolanda Vendrell, Edward W Tate, Paul R Elliott, Graham M West, Darragh P O'Brien, Eidarus Salah, Andrew P Turnbull, Christopher J Schofield, Benedikt M Kessler, Lennart Brewitz, Adán Pinto-Fernández","doi":"10.1038/s44386-026-00092-z","DOIUrl":"10.1038/s44386-026-00092-z","url":null,"abstract":"Deubiquitinases (DUBs) play key roles in human pathologies, including cancer, infectious, autoimmune, and neurodegenerative diseases. The progress of potent and selective active site-targeting DUB inhibitors into clinical trials has demonstrated the therapeutic opportunities of such molecules; however, the shared catalytic geometry among DUB family members poses a challenge for achieving inhibitor selectivity. We describe a high-throughput, DUB-focused, activity-based proteomics workflow to identify new types of cysteine-reactive DUB inhibitors. We demonstrate the potential of αβ,α'β'-diepoxyketones (DEKs) and ubiquitin-derived covalently reacting alkynes as the first selective, cell-active compounds targeting USP47, OTUD7B (Cezanne), and USP5. These DUBs are reported to have critical roles in inflammasome formation, hypoxia, and viral replication, respectively. The identified compounds phenocopy these findings, demonstrating the tractability of these DUBs as immunotherapeutic targets.","PeriodicalId":520448,"journal":{"name":"NPJ drug discovery","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13710844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149280628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Publisher Correction: RUNX2 inhibitor CADD522 improves bone microarchitecture and lipid metabolism in post-menopausal bone loss. 发布者更正：RUNX2抑制剂CADD522改善绝经后骨质流失的骨微结构和脂质代谢。

NPJ drug discovery Pub Date : 2026-10-22 DOI: 10.1038/s44386-026-00088-9

Adel Ersek, Myoung Sook Kim, Caterina Suelzu, Isabelle Piec, Aerielle Matsangos, Elmar Nurmemmedov, Emma C Bull, Tabitha Bartlett, Rachel Dunn, James R Dick, Rena Lapidus, Danielle M Copeman, Jonathan C Y Tang, Paul G Crichton, Matthew G Pontifex, William D Fraser, Nicole J Horwood, Antonino Passaniti, Darrell Green

引用次数: 0

Drug repurposing in hereditary ataxia. 遗传性共济失调的药物再利用。

NPJ drug discovery Pub Date : 2026-10-12 DOI: 10.1038/s44386-026-00079-w

Lorenzo Cipriano, Matteo Rossi Sebastiano, Filippo Maria Santorelli

引用次数: 0

Proportionate evidence in biosimilar development: when a comparative efficacy study can still change the regulatory conclusion. 生物仿制药开发中的比例证据：当比较疗效研究仍然可以改变监管结论时。

NPJ drug discovery Pub Date : 2026-10-12 DOI: 10.1038/s44386-026-00080-3

Sarfaraz K Niazi

{"title":"Proportionate evidence in biosimilar development: when a comparative efficacy study can still change the regulatory conclusion.","authors":"Sarfaraz K Niazi","doi":"10.1038/s44386-026-00080-3","DOIUrl":"10.1038/s44386-026-00080-3","url":null,"abstract":"Biosimilar regulation was established using a systematic, stepwise framework in which clinical comparisons addressed residual uncertainties following comprehensive quality and pharmacokinetic assessments. Advances in analytical resolution, clinical pharmacology, and over two decades of regulatory expertise have substantially mitigated this residual uncertainty. This publication examines circumstances in which a comparative efficacy study could still influence regulatory decisions. It presents four original analyses: a quantitative comparison of the nominal resolution of selected analytical methodologies, combined with predefined equivalence criteria, within specific clinical programs that operate at disparate scales and are used solely to demonstrate respective resolution and acceptance thresholds. Additionally, an audit of publicly available regulatory outcomes identifies 100 United States 351(k)-licensed biosimilar and interchangeable products, alongside 149 authorized European biosimilars. It also classifies 16 European nonpositive initial outcomes: nine primarily driven by quality, manufacturing, or product bridging issues; two involving clinical pharmacology or overall comparability; one following a positive opinion; and four lacking sufficient public detail. Notably, no case identified a failed comparative efficacy study as the sole decisive factor, a conclusion limited by excluding programs abandoned before filing from the dataset. An analysis of participant burden estimates indicates an aggregate of more than 10,000 enrollments for programs approved through 2019. A Bayesian value of information model shows that, under a defined base case, the net benefit of such a study diminishes once prior evidence indicates that clinical similarity substantially exceeds the decision threshold. The framework continues to emphasize targeted clinical evidence relevant to unresolved mechanisms, uncharacterized local exposure, potential immune risks, or unaddressed population-specific questions.","PeriodicalId":520448,"journal":{"name":"NPJ drug discovery","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149168519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The rise of agentic AI in drug discovery from static tools to autonomous virtual scientists. 人工智能在药物发现中的兴起，从静态工具到自主的虚拟科学家。

NPJ drug discovery Pub Date : 2026-10-12 DOI: 10.1038/s44386-026-00075-0

Donghai Zhao, Meijing Fang, Lexiao Mao, Yuchen Zhu, Qun Su, Hui Shi, Hongxia Xu, Lanqing Li, Tingjun Hou, Chang-Yu Hsieh

引用次数: 0

Efflux modulation as an antimicrobial strategy: mechanisms and translational perspectives. 外排调节作为抗菌策略：机制和翻译的观点。

NPJ drug discovery Pub Date : 2026-10-12 DOI: 10.1038/s44386-026-00083-0

Waleska Stephanie da Cruz Nizer, Cesar Augusto Roque-Borda, Chongbing Liao, Heitor Leocádio de Souza Rodrigues, Subham Kumar Vishwakarma, Zidane Qriouet, Andreia Bagliotti Meneguin, Fernando Rogério Pavan

引用次数: 0

Benchmarking Boltz-2 for relative kinase-inhibitor interaction patterns across conformational states and resistance mutations. 对Boltz-2在构象状态和抗性突变中的相对激酶抑制剂相互作用模式进行基准测试。

NPJ drug discovery Pub Date : 2026-10-12 DOI: 10.1038/s44386-026-00086-x

Atsushi Suenaga, Noriaki Okimoto

{"title":"Benchmarking Boltz-2 for relative kinase-inhibitor interaction patterns across conformational states and resistance mutations.","authors":"Atsushi Suenaga, Noriaki Okimoto","doi":"10.1038/s44386-026-00086-x","DOIUrl":"10.1038/s44386-026-00086-x","url":null,"abstract":"Generative structure-prediction models can directly predict protein-ligand complexes from sequence and ligand information, but their ability to capture pharmacologically relevant kinase-inhibitor interactions remains incompletely understood. We systematically evaluated Boltz-2 using curated biochemical IC50 measurements across eight human kinases, nine clinically used inhibitors, and representative resistance mutations. Although predicted log10(IC50) values showed a compressed dynamic range relative to experimental measurements, mutation-dependent shifts in inhibitor sensitivity, inhibitor selectivity patterns, and overall potency rankings showed substantial agreement with the experimental patterns within the present benchmark. Predicted binding probability showed good discrimination between binder and non-binder pairs within the present benchmark and a consistent inverse relationship with experimental potency. Structural analyses showed that ligand-pose variability was associated with prediction behavior within the evaluated kinase-inhibitor systems, even when kinase-domain structures showed close agreement with the corresponding experimental structures. Larger ligand RMSD values were not associated with larger prediction errors in magnitude, but were linked to systematic shifts in prediction bias, indicating that ligand-pose accuracy and predictive utility are not equivalent measures of Boltz-2 performance. These findings suggest that, within the present benchmark, relative kinase-inhibitor interaction patterns were reproduced more consistently than absolute potency values. We provide a framework for interpreting Boltz-2 outputs within the kinase-inhibitor systems examined here.","PeriodicalId":520448,"journal":{"name":"NPJ drug discovery","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149168437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0