ACS Chemical Biology最新文献

{"title":"","authors":"Michael W. Founds, Olivia L. Murtagh, R. Justin Grams, Zhihong Li, Anthony M. Ciancone, Robert J Seal and Ku-Lung Hsu*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00231","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144469158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"Subhradeep Bhar, Dilip V. Prajapati, Melisa S. Gonzalez, Chi-Su Yoon, Kevin Mai, Laura S. Bailey, Kari B. Basso and Rebecca A. Butcher*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00126","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144469161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"Zhihang Shen, Xiaozhi Yang, Gustavo Seabra, Xueyong Xu, Jiawei Dong, Jason Orr Brant, Wei Zhou, Juan Guan, Wen Jiang and Chenglong Li*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00160","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144469170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery and Characterization of Small Molecule Inhibitors Targeting Exonuclease 1 for Homologous Recombination-Deficient Cancer Therapy.","authors":"Yixing Wang, Jessica D Hess, Chen Wang, Lingzi Ma, Megan Luo, Jennifer Jossart, John J Perry, David Kwon, Zhe Wang, Xinyu Pei, Changxian Shen, Yingying Wang, Mian Zhou, Holly Yin, David Horne, André Nussenzweig, Li Zheng, Binghui Shen","doi":"10.1021/acschembio.5c00117","DOIUrl":"10.1021/acschembio.5c00117","url":null,"abstract":"<p><p>Human exonuclease 1 (EXO1), a member of the structure-specific nuclease family, plays a critical role in maintaining genome stability by processing DNA double-strand breaks (DSBs), nicks, and replication intermediates during DNA replication and repair. As its exonuclease activity is essential for homologous recombination (HR) and replication fork processing, EXO1 has emerged as a compelling therapeutic target, especially in cancers marked by heightened DNA damage and replication stress. Through high-throughput screening of 45,000 compounds, we identified seven distinct chemical scaffolds that demonstrated effective and selective inhibition of EXO1. Representative compounds from two of the most potent scaffolds, C200 and F684, underwent a comprehensive docking analysis and subsequent site-directed mutagenesis studies to evaluate their binding mechanisms. Biochemical assays further validated their potent and selective inhibition of the EXO1 nuclease activity. Tumor cell profiling experiments revealed that these inhibitors exploit synthetic lethality in BRCA1-deficient cells, emphasizing their specificity and therapeutic potential for targeting genetically HR-deficient (HRD) cancers driven by deleterious mutations in HR genes like BRCA1/2. Mechanistically, EXO1 inhibition suppressed DNA end resection, stimulated the accumulation of DNA double-strand breaks, and triggered S-phase PARylation, effectively disrupting DNA repair pathways that are essential for cancer cell survival. These findings establish EXO1 inhibitors as promising candidates for the treatment of HRD cancers and lay the groundwork for the further optimization and development of these compounds as targeted therapeutics.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1258-1272"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144074837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serendipitous and Systematic Chemoproteomic Discovery of MBLAC2, HINT1, and NME1-4 Inhibitors from Histone Deacetylase-Targeting Pharmacophores.","authors":"Severin Lechner, Shuyao Sha, Jigar Paras Sethiya, Patrycja Szczupak, Rafal Dolot, Santosh Lomada, Amirhossein Sakhteman, Johanna Tushaus, Polina Prokofeva, Michael Krauss, Ferdinand Breu, Katharina Vögerl, Martin Morgenstern, Martin Hrabě de Angelis, Volker Haucke, Thomas Wieland, Carston Wagner, Guillaume Médard, Franz Bracher, Bernhard Kuster","doi":"10.1021/acschembio.5c00108","DOIUrl":"10.1021/acschembio.5c00108","url":null,"abstract":"<p><p>Metalloenzyme inhibitors often incorporate a hydroxamic acid moiety to bind the bivalent metal ion cofactor within the enzyme's active site. Recently, inhibitors of Zn²⁺-dependent histone deacetylases (HDACs), including clinically advanced drugs, have been identified as potent inhibitors of the metalloenzyme MBLAC2. However, selective chemical probes for MBLAC2, which are essential for studying its inhibitory effects, have not yet been reported. To discover highly selective MBLAC2 inhibitors, we conducted chemoproteomic target deconvolution and selectivity profiling of a library of hydroxamic acid-type molecules and other metal-chelating compounds. This screen revealed MBLAC2 as a frequent off-target of supposedly selective HDAC inhibitors, including the HDAC6 inhibitor SW-100. Profiling a focused library of SW-100-related phenylhydroxamic acids led to identifying two compounds, KV-65 and KV-79, which exhibit nanomolar binding affinity for MBLAC2 and over 60-fold selectivity compared to HDACs. Interestingly, some phenylhydroxamic acids were found to bind additional off-targets. We identified KV-30 as the first drug-like inhibitor of the histidine triad nucleotide-binding protein HINT1 and confirmed its mode of inhibition through a cocrystal structure analysis. Furthermore, we report the discovery of the first inhibitors for the undrugged nucleoside diphosphate kinases NME1, NME2, NME3, and NME4. Overall, this study maps the target and off-target landscape of 53 metalloenzyme inhibitors, providing the first selective MBLAC2 inhibitors. Additionally, the discovery of pharmacophores for NME1-4 and HINT1 establishes a foundation for the future design of potent and selective inhibitors for these targets.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1247-1257"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186257/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA Alkylation, Cross-Linking, and Cancer Cell Killing by a Quinoxaline-<i>N</i>-Mustard Conjugate.","authors":"Chandra Sova Mandi, Dipendu Patra, Tanhaul Islam, Bhim Majhi, Kent S Gates, Sanjay Dutta","doi":"10.1021/acschembio.4c00734","DOIUrl":"10.1021/acschembio.4c00734","url":null,"abstract":"<p><p>Nitrogen mustards are a family of clinically used anticancer drugs that contain a DNA-alkylating bis(2-chloroethyl)amino group. Appending the bis(2-chloroethyl)amino alkylating agent to noncovalent DNA-binding groups such as intercalators, polyamides, or polyamines has the potential to yield DNA-targeted anticancer agents with improved potency. In the work reported here, substituted quinoxaline groups were explored as minimal intercalators expected to confer noncovalent DNA-binding properties on a bis(2-chloroethyl)anilino mustard alkylating unit. A quinoxaline unit with a cationic dimethylamino-containing side chain was found to be a more potent DNA-alkylating and cross-linking agent than the clinically used mustard chlorambucil (<b>Chb</b>). The results of dye displacement and multiple DNA alkylation assays showed that the quinoxaline ring binds noncovalently to duplex DNA, likely via intercalation. The quinoxaline-mustard conjugate was more active than <b>Chb</b> against a variety of cancer cell lines. Evidence is presented, showing that both the quinoxaline-mustard and the clinically used drug <b>Chb</b> formed aggregates in aqueous buffer; however, the results clearly show that the propensity to form aggregates clearly does not abrogate the DNA-alkylating properties or bioactivity of these compounds.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1171-1180"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Experimental and Computational Evaluation of Nicotinamide Cofactor Biomimetics.","authors":"Karissa C Kenney, Tyler P LaFortune, Sourav Majumdar, Edgar M Manriquez, Arjun S Pamidi, Courtnie S Kom, Jason E Garrido, Edgar S Villa, Filipp Furche, Gregory A Weiss","doi":"10.1021/acschembio.5c00174","DOIUrl":"10.1021/acschembio.5c00174","url":null,"abstract":"<p><p>Oxidoreductase enzymes are widely used biocatalysts due to their high enantioselectivity and broad substrate compatibility in useful transformations. Many oxidoreductases require nicotinamide cofactors (i.e., NAD(P)H). To replace this costly natural cofactor, synthetic nicotinamide cofactor biomimetics (NCBs) offer different shapes, binding affinities, and reducing potentials that exceed the capabilities of wild-type NAD(P)H. However, the ill-defined structure-activity relationships (SARs) of various NCBs slow rationally guided innovation, such as customized reducing potentials. Here, we dissect two essential elements of NCB design, holding the nicotinamide invariant. First, the linker length between the nicotinamide and an unconjugated aromatic ring uncovered unexpected benefits to redox activity for two or three carbon linkers. Second, substitution on this unconjugated aryl group (Ring 2) might not be expected to affect activity. However, SAR trends demonstrate substantial benefits to reductive potential conferred by electron-donating functionalities on Ring 2. Furthermore, catalysis by two enzymes demonstrates enzyme-dependent tolerance or sensitivity to the NCB structures. Density functional theory (DFT) and computational modeling provide a theoretical framework to understand and build upon these observations. Ring 2 reaches up to the nicotinamide to stabilize its positive charge after oxidation through π-π stacking and charge transfer. Thus, the systematic examination of NCB's stability, electrochemical redox potentials, and kinetics uncovers trends for the improved design of NCBs.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1361-1370"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186268/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144256625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Photoaffinity Ligand of Cystic Fibrosis Corrector VX-445 Identifies SCCPDH as an Off-Target.","authors":"Minsoo Kim, Kwangho Kim, Jesun Lee, Lea A Barny, Toya D Scaggs, Ian M Romaine, KyuOk Jeon, Simona G Codreanu, Stacy D Sherrod, John A McLean, Anjaparavanda P Naren, Gary A Sulikowski, Lars Plate","doi":"10.1021/acschembio.5c00157","DOIUrl":"10.1021/acschembio.5c00157","url":null,"abstract":"<p><p>Cystic fibrosis (CF) pharmacological correctors improve the cystic fibrosis transmembrane conductance regulator (CFTR) protein trafficking and function. Several side effects of these correctors and adverse drug interactions have been reported, emphasizing the need to understand off-targets. We synthesized VU439, a functionalized photoaffinity ligand (PAL) of VX-445. Chemoproteomics analysis by mass spectrometry (MS) was used to identify cross-linked proteins in CF bronchial epithelial cells expressing F508del CFTR. We identified saccharopine dehydrogenase-like oxidoreductase (SCCPDH), an uncharacterized putative oxidoreductase, as a VX-445-specific off-target. We also characterized changes in the metabolomic profiles of cells overexpressing SCCPDH to determine the consequence of binding of VX-445 to SCCPDH. These data show dysregulation of amino acid metabolism and a potential inhibitory activity of VX-445 on SCCPDH. The identified off-target may explain the exacerbation of psychological symptoms observed in the clinic, thus emphasizing the need for further optimization of correctors.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein Phosphatase 5-Recruiting Chimeras for Accelerating Tau Dephosphorylation.","authors":"Jinying Gu, Chenxi He, Zeyu Han, Qifei Huang, Yanyi He, Yun Lu, Qidong You, Qiuyue Zhang, Lei Wang","doi":"10.1021/acschembio.5c00165","DOIUrl":"10.1021/acschembio.5c00165","url":null,"abstract":"<p><p>Hyperphosphorylation of proteins is implicated in various diseases, such as phosphorylated Tau (p-Tau), which is the main cause of Alzheimer's disease (AD). Dephosphorylation strategies have still been limited. Currently, phosphatase recruitment chimeras (PHORCs) have become a potential strategy for accelerating the dephosphorylation of proteins. However, PHORCs are still in the proof-of-concept stage. The paucity of available phosphatase effectors and the lack of effective methods to identify the appropriate length of the linker impede the development of PHORCs. Protein phosphatase 5 (PP5) is responsible for dephosphorylation of p-Tau in the brain. PP5 is distinct from other phosphatases, with a unique activation mechanism. We demonstrated that PP5 can be simultaneously recruited and activated for the design of PHORCs, exhibiting a synergistic advantage for accelerating dephosphorylation of p-Tau. Moreover, we attempted computation-aided prediction methods to obtain the potential length of the linker, promoting the rational design of PHORCs. Therefore, our study provides critical insights into the development of PHORCs and proposes new ideas for accelerating the design of heterotrimeric chimeras.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1347-1360"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"Ayush Srivastava,&nbsp;Maximilian Beyer,&nbsp;Colby Hladun,&nbsp;Rebekah Tardif,&nbsp;Aneeta Arshad,&nbsp;Costel C. Darie,&nbsp;Yeonni Zoo,&nbsp;Georgia C. Papaefthymiou,&nbsp;Liu Weijing,&nbsp;Rosa Viner,&nbsp;Paolo Arosio and Fadi Bou-Abdallah*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00183","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144469165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}