RSC medicinal chemistry最新文献

{"title":"Design, synthesis and evaluation of pyrrolobenzodiazepine (PBD)-based PROTAC conjugates for the selective degradation of the NF-κB RelA/p65 subunit.","authors":"Peiqin Jin, Md Mahbub Hasan, Andrea G S Pepper, Simon Mitchell, Khondaker Miraz Rahman, Chris Pepper","doi":"10.1039/d5md00316d","DOIUrl":"10.1039/d5md00316d","url":null,"abstract":"<p><p>NF-κB signalling is frequently dysregulated in human cancers making it an attractive therapeutic target. Despite concerted efforts to generate NF-κB inhibitors, direct pharmacological inhibition of the kinases mediating canonical NF-κB has failed due to on-target toxicities in normal tissues. So, alternative strategies, designed to target specific components of the NF-κB signalling machinery, have the potential to selectively inhibit tumour cells whilst reducing the toxicities associated with broad inhibition of NF-κB in non-malignant cells. Here we present evidence that a C8-linked pyrrolobenzodiazepine (PBD) containing proteolysis-targeting chimera (PROTAC) selectively degrades the NF-κB subunit, RelA/p65, in a proteasome-dependent manner. Our lead PROTAC (JP-163-16, 15d) showed cytotoxicity with mean LC₅₀ values of 2.9 μM in MDA-MB-231 cells, 0.14 μM in MEC-1 cells and 0.23 μM in primary chronic lymphocytic leukaemia cells. In contrast, 15d was two-logs less toxic in primary B- and T-lymphocytes (mean LD₅₀ 19.1 μM and 36.4 μM, respectively). Importantly, the development of 15d, by conjugating the C8-linked PBD with a cereblon-targeting ligand using a five-carbon linker, abolished the ability of the C8-linked PBD to bind to DNA, whilst demonstrating cytotoxicity in cancer cells associated with the degradation of RelA/p65. Mechanistically, 15d displayed PROTAC credentials through the selective degradation of NF-κB RelA/p65 in a proteasome-dependent manner and showed a five-fold reduction in potency in the cereblon deficient, lenalidomide resistant, myeloma cell line, RPMI-8226. To our knowledge, this work describes the first PROTAC capable of selective degradation of a single NF-κB subunit and highlights the therapeutic potential of our strategy for the treatment of RelA/p65-dependent tumours.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12117510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of novel antimyeloma agents targeting TRIP13 by molecular modeling and bioassay.","authors":"Samuel Jacob Bunu, Haiyan Cai, Zhaoyin Zhou, Yanlei Zhang, Yue Lai, Guanli Wang, Dongliang Song, Chengkun Wu, Hang Zheng, Zhijian Xu, Jumei Shi, Weiliang Zhu","doi":"10.1039/d4md01008f","DOIUrl":"https://doi.org/10.1039/d4md01008f","url":null,"abstract":"<p><p>Thyroid hormone receptor-interacting protein-13 (TRIP13) is an AAA⁺ ATPase that regulates protein complex assembly and disassembly and is known to be a chromosomal instability gene with the ability to repair DNA double-strand breaks. TRIP13 overexpression has been linked to the proliferation and development of many human malignancies, including multiple myeloma (MM). Accordingly, TRIP13 is recognized as a potential drug target for anticancer drug development. Although some TRIP13 inhibitors have been reported, none are under clinical trial or approved for clinical use. This study aimed to identify novel small molecules as potential TRIP13 inhibitors structurally different from previously reported compounds through molecular modeling and bioassays. As a result, five compounds were successfully identified as novel TRIP13 inhibitors. F368-0183 showed the best antiproliferative activity with IC₅₀ = 5.25 μM (NCI-H929 cell line), comparable with the positive control DCZ0415 (IC₅₀ = 9.64 μM). Also, the cellular thermal shift assay confirmed that this compound could interact with the TRIP13 protein in MM cells. In addition, the AAA⁺ ATPase inhibitory bioassay demonstrated that the five compounds had better inhibitory activity than DCZ0415, having strong correlations with the calculated free energy perturbation (FEP). Further molecular dynamics simulation studies revealed that the novel compounds could significantly interact with 12 residues of TRIP13, especially R386, L139, R389, L135, S138, Y141, and G385. We also assessed the F368-0183 inhibition on a kinase panel, no other targets were found, but the potential binding to other target proteins of these compounds cannot be totally excluded. Therefore, the new molecular scaffolds of these compounds, their efficacy in suppressing MM cell line proliferation, and the displayed TRIP13 AAA⁺ ATPase inhibitory properties provide important clues for developing novel TRIP13-based multi-target anti-MM drugs.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12053442/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144034657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Niclosamide: CRL4^AMBRA1 mediated degradation of cyclin D1 following mitochondrial membrane depolarization.","authors":"Seemon Coomar, Jessica A Gasser, Mikołaj Słabicki, Katherine A Donovan, Eric S Fischer, Benjamin L Ebert, Dennis Gillingham, Nicolas H Thomä","doi":"10.1039/d5md00054h","DOIUrl":"https://doi.org/10.1039/d5md00054h","url":null,"abstract":"<p><p>Targeted protein degradation has emerged as a promising approach in drug discovery, utilizing small molecules like molecular glue degraders to harness the ubiquitin-proteasome pathway for selective degradation of disease-driving proteins. Based on results from proteomics screens we investigated the potential of niclosamide, an FDA-approved anthelmintic drug with a 50 year history in treating tapeworm infections, as a molecular glue degrader targeting the proto-oncogene cyclin D1. Proteomics screens in HCT116 colon carcinoma and KELLY neuroblastoma cells, found that niclosamide induces rapid cyclin D1 degradation through a mechanism involving the ubiquitin-proteasome pathway. A genetic CRISPR screen identified the E3 ligase CRL4^AMBRA1 as a key player in this process. Structure-activity relationship studies highlighted critical features of niclosamide necessary for cyclin D1 degradation, demonstrating a correlation between mitochondrial membrane potential (MMP) disruption and cyclin D1 downregulation. Notably, various mitochondrial uncouplers and other compounds with similar drug sensitivity profiles share this correlation suggesting that MMP disruption can trigger cyclin D1 degradation, and that the cellular signal driving the degradation differs from previously described mechanism involving CRL4^AMBRA1. Our findings underscore the complexities of proteostatic mechanisms and the multitude of mechanisms that contribute to degrader drug action.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12054360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144028060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrocyclic RGD-peptides with high selectivity for α_vβ₃ integrin in cancer imaging and therapy.","authors":"Xiaozhong Cheng, Chen Li, Haofei Hong, Zhifang Zhou, Zhimeng Wu","doi":"10.1039/d5md00280j","DOIUrl":"https://doi.org/10.1039/d5md00280j","url":null,"abstract":"<p><p>Integrins, particularly the α_vβ₃ subtype, are critical receptors involved in cell adhesion, migration, and signaling, playing a significant role in tumor progression and metastasis. Despite extensive research into integrin-targeted therapies, challenges remain in developing ligands that exhibit high selectivity for α_vβ₃ over other integrin subtypes, such as α_vβ₅. This study employs a one-pot sortase A-mediated on-resin peptide cleavage and <i>in situ</i> cyclization method to synthesize two generations of macrocyclic RGD-peptide libraries. Systematic screening through surface plasmon resonance and cell-based competition assays identified the lead compound, c-(G5RGDKcLPET), which demonstrated high affinity and selectivity for α_vβ₃. Additionally, the optimized cyclic peptide was functionalized with a fluorescent dye (Cy5) and the cytotoxic drug monomethyl auristatin E (MMAE), enhancing its potential for cancer imaging and targeted therapy. This work contributes a novel platform for developing integrin-targeted diagnostics and therapeutics, highlighting the importance of macrocyclic peptides in cancer treatment strategies.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144080063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A context-based matched molecular pair analysis identifies structural transformations that reduce CYP1A2 inhibition.","authors":"Janvi A Raut, Vaibhav A Dixit","doi":"10.1039/d4md01012d","DOIUrl":"10.1039/d4md01012d","url":null,"abstract":"<p><p>Cytochrome P450 1A2 (CYP1A2) metabolizes ∼10-15% of FDA-approved drugs. Available quantitative structure-activity relationship (QSAR) and machine learning methods offer little design insights to reduce CYP1A2 inhibition. We performed matched molecular pair analysis (MMPA) on the CYP1A2 inhibition dataset (ChEMBL3356) and identified key structural transformations. A chemical context-based analysis was performed using Kramer's method to tackle the limitations of the global MMPA. The global MMPA agreed with earlier QSAR studies (influence of H to F, Me, OMe, and OH transformations). Our results show that the effect of these transformations depends on the local chemical environment. The H to Me transformation reduced the inhibition in three pharmacologically important scaffolds (<i>e.g.</i>, indanylpyridine). Structure-based analysis (docking) showed that the interaction of the heteroatoms with Heme-Fe is influenced by useful transformations. Overall, this work presents the first context-based analysis of the CYP1A2 dataset and offers novel medicinal chemistry insights useful for lead optimization.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12107391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proximity-induced membrane protein degradation for cancer therapies.","authors":"Dingpeng Zhang, Zhen Wang, Hiroyuki Inuzuka, Wenyi Wei","doi":"10.1039/d5md00141b","DOIUrl":"10.1039/d5md00141b","url":null,"abstract":"<p><p>The selective modulation of membrane proteins presents a significant challenge in drug development, particularly in cancer therapies. However, conventional small molecules and biologics often face significant hurdles in effectively targeting membrane-bound proteins, largely due to the structural complexity of these proteins and their involvement in intricate cellular processes. In light of these limitations, proximity-induced protein modulation has recently emerged as a transformative approach. It leverages molecule-induced proximity strategies to commandeer endogenous cellular machinery for precise protein manipulation. One of these modulatory strategies is protein degradation, wherein membrane-targeting degraders derived from proximity-induction approaches offer a unique therapeutic avenue by inducing the irreversible removal of key oncogenic and immune-regulatory proteins to combat cancer. This review explores the fundamental principles underlying proximity-driven membrane protein degradation, highlighting key strategies such as LYTACs, PROTABs, TransTACs, and IFLD that are reshaping targeted cancer therapy. We discuss recent technological advancements in the application of proximity-induced degraders across breast cancer, lung cancer, immunotherapy, and other malignancies, underscoring how these innovative approaches have demonstrated significant therapeutic potential. Lastly, while these emerging technologies offer significant promise, they still face substantial limitations, including drug delivery, selectivity, and resistance mechanisms that need to be addressed to achieve successful clinical translation.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12066958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144049888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research prospects and AI-driven strategies for metal-organic framework-hydrogel composite materials in cancer treatment.","authors":"Zijun Zhang, Yuelin Zhang, Taiwei Liang, Jiajia Zhang, Weidong Liu, Ying Pan, Jianqiang Liu, Xiaoxiu Li","doi":"10.1039/d5md00207a","DOIUrl":"10.1039/d5md00207a","url":null,"abstract":"<p><p>Metal-organic frameworks (MOFs) as emerging materials with highly tunable structures, large specific surface areas, and abundant pores show unique advantages in gas storage, catalysis, and drug delivery. Hydrogels are a class of materials consisting of polymers or small molecules that can trap a large amount of water and are thus widely used in biomedical applications owing to their high water content, good biocompatibility, biotissue-like softness and elasticity, and low immunogenicity. Consequently, composite materials formed by combining MOFs with hydrogels have been rapidly developed for cancer therapy. We have carried out considerable work on this type of composite material, exploring various combinations and investigating different treatment modalities, such as chemotherapy, immunotherapy, targeted therapy and combination therapy. Particularly, artificial intelligence (AI) technology was employed to characterize and enhance the therapeutic efficacy of the materials. This review first introduces the basic properties of MOFs and hydrogels and the role played by AI technology in their development. Subsequently, we describe the types, characteristics, applications, and challenges of MOF-hydrogel combinations, focusing on the research progress of various types of cancer treatments based on MOF hydrogels and the application of AI technology in this field. With the deepening of research, the development of smarter and more efficient MOF-hydrogel materials and the in-depth exploration of the application of AI technology in cancer therapy are expected to realize the precise treatment and effective control of cancer and bring new hope to cancer patients.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biological assessments of novel ultrasound-synthesized 2-arylbenzimidazole derivatives: antiproliferative and antibacterial effects.","authors":"Ivana Sokol, Anja Rakas, Dajana Kučić Grgić, Leentje Persoons, Dirk Daelemans, Tatjana Gazivoda Kraljević","doi":"10.1039/d5md00106d","DOIUrl":"https://doi.org/10.1039/d5md00106d","url":null,"abstract":"<p><p>This paper describes ultrasound synthesis, structural characterization and biological activity of new derivatives of 2-arylbenzimidazole 12-27 and 1,2,3-triazole derivatives of 2-arylbenzimidazole 28-33. The tautomeric structures of the prepared target compounds were confirmed by ¹H- and ¹³C-NMR spectroscopy as well as by two-dimensional NOESY, HSQC and HMBC methods. The synthesized compounds underwent <i>in vitro</i> antiproliferative assays, revealing that compound 23 exhibited the highest potency against chronic myeloid leukemia cells (K-562, IC₅₀ = 2.0 μM) and non-Hodgkin's lymphoma cells (Z-138, IC₅₀ = 2.0 μM). Compound 23 was further evaluated for cytotoxicity on normal peripheral blood mononuclear cells (PBMC), and its mechanism of action was investigated. The antibacterial properties of the synthesized compounds were assessed against both Gram-positive and Gram-negative bacterial strains. Derivatives 15-17 exhibited significant selective antibacterial activity against the Gram-positive bacterium <i>Enterococcus faecalis</i> (MIC = 0.25-1 μg mL^-1). Additionally, among the 1,2,3-triazole derivatives of 2-arylbenzimidazole, compounds 28 and 30 demonstrated strong selective activity against <i>Enterococcus faecalis</i> (MIC = 0.25 μg mL^-1).</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12062833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144028031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Grassystatin G, a new cathepsin D inhibitor from marine cyanobacteria: discovery, synthesis, and biological characterization.","authors":"Lobna A Elsadek, Gustavo Seabra, Valerie J Paul, Hendrik Luesch","doi":"10.1039/d5md00017c","DOIUrl":"https://doi.org/10.1039/d5md00017c","url":null,"abstract":"<p><p>Through ongoing investigations of marine cyanobacteria, a prolific source of structurally diverse secondary metabolites, we isolated grassystatin G (1), a new statine-containing linear peptide, closely related to the cathepsin E (CatE) inhibitors grassystatins A-F, some of which may function as CatE probes. The planar structure of 1 was determined by analysis of 1D, 2D NMR and MS/MS fragmentation data, and is structurally distinct from its analogs by being shorter and containing a hydrophobic residue (Val) adjacent to the statine unit instead of a polar residue (Asn, Gln). We employed chiral HPLC analysis and modified Marfey's method to assign the absolute configuration of constituent amino acids, suggesting the presence of <i>N</i>-Me-l-Phe instead of <i>N</i>-Me-d-Phe in other grassystatins. To prove the structure and overcome the lack of material for further biological studies and mechanistic characterization, we developed a 3 + 3 convergent synthesis and have accessed the peptide with an overall yield of 19% using standard peptide coupling. As the statine moiety is a known pharmacophore with an inhibitory effect against aspartic proteases, we screened grassystatin G against a panel of human and virus aspartic proteases. In contrast to grassystatins A-F, preferentially targeting CatE over CatD with 18-66-fold selectivity, grassystatin G displayed 2-fold selectivity for CatD over CatE, suggesting that the key structural differences may be exploited for CatD probe design. Docking and molecular dynamics provided insights into the structural features responsible for the selectivity towards CatD. CatD is well-documented to play a role in cancer proliferation and metastasis, particularly in the context of breast cancer. We tested grassystatin G against MDA-MB-231 triple-negative breast cancer cells and demonstrated its cooperative effects with TRAIL. RNA-seq highlighted the potential pathways and molecular mechanisms governed by grassystatin G alone and in combination with TRAIL.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12024474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144051256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and anti-mycobacterial activity of novel medium-chain β-lactone derivatives: a multi-target strategy to combat <i>Mycobacterium abscessus</i>.","authors":"Thomas Francis, Christina Dedaki, Phoebe Ananida-Dasenaki, Dimitra Bolka, Kanellos Albanis, Filippos Foteinakis, Julie Mezquida, Marie Hance, Alexandros Athanasoulis, Anna-Krinio Papagiorgou, Ioanna-Foteini Karampoula, George Georgitsis, Celia Jardin, Stéphane Audebert, Luc Camoin, Céline Crauste, Stéphane Canaan, Victoria Magrioti, Jean-François Cavalier","doi":"10.1039/d5md00102a","DOIUrl":"10.1039/d5md00102a","url":null,"abstract":"<p><p>The constant emergence of drug-resistant mycobacteria, together with the lack of new antibiotics entering the market, has become a global public health problem that threatens the effective treatment of infectious diseases. The development of single molecules targeting different proteins should significantly reduce the emergence of resistant strains, and therefore represent a promising strategy to overcome such an issue. In this challenging context, a new series of 30 lipophilic compounds based on the β-lactone-core has been synthesized by varying the nature of the substituents on the lactone ring. The evaluation of their antibacterial activity against <i>M. tuberculosis</i> and <i>M. abscessus</i>, two major pathogenic mycobacteria, highlighted potential candidates. The VM038, VM040 and VM045 were active only against <i>M. tuberculosis</i>, while VM025, VM026 and VM043 inhibited the growth of both <i>M. tuberculosis</i> and the S and R variants of <i>M. abscessus</i>. Competitive click chemistry activity-based protein profiling revealed several potential <i>M. abscessus</i> target enzymes of VM043, the best extracellular growth inhibitor. Finally, when tested against intracellular bacteria, although VM043 was found inactive, VM025 & VM026 proved to be potent and promising inhibitors of intramacrophagic <i>M. abscessus</i> growth with minimal inhibitory concentrations (MIC_50Raw) comparable to the standard antibiotic imipenem. Overall, these results strengthen the added value of our VM β-lactone derivatives not only in the fight against pathogenic mycobacteria, leading to the arrest of <i>M. abscessus</i> and/or <i>M. tuberculosis</i> growth through multitarget enzyme inhibition, but also as efficient probes to identify novel potential therapeutic targets using chemoproteomics approaches.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12101465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}