ACS Bio & Med Chem Au最新文献

{"title":"Side-by-Side Comparison of Different Thiol Bioconjugation Strategies for the Chemoselective Radiolabeling of Human Serum Albumin with Zirconium-89","authors":"Julia Kronberger,&nbsp;Barbora Neuzilova,&nbsp;Anja Federa,&nbsp;Manuel Tieber,&nbsp;Amando Palombo,&nbsp;Marie R. Brandt,&nbsp;Petra Heffeter,&nbsp;Christian R. Kowol,&nbsp;Milos Petrik,&nbsp;Thomas L. Mindt","doi":"10.1021/acsbiomedchemau.6c00002","DOIUrl":"10.1021/acsbiomedchemau.6c00002","url":null,"abstract":"<p>Different bioconjugation strategies are available forthe cysteine(Cys)-specific functionalization of proteins with different payloads,including imaging probes and (pro-)drugs. Most commonly applied linkersinclude maleimides (mal); however, because of the sometimes-observedinstability of the formed thiosuccinimidyl linkage, its suitabilityfor in vivo applications has been challenged. Consequently, severalalternatives have been developed and compared to mal as a benchmark,yet examples of a direct comparison among new methodologies are scarce.We herein report a comparison of the use of mal, phenyloxadiazolemethyl sulfone (PODS), and vinylketone (VK) as functional groups forthe thiol-specific functionalization of human serum albumin (HSA)via its available free Cys³⁴. Bifunctional chelating agents(BFCA) based on DFO*, identical in all regards but the functionalgroup for bioconjugation, were prepared and conjugated to HSA andthe obtained DFO*-HSA conjugates were radiolabeled with Zirconium-89(⁸⁹Zr) for positron emission tomography (PET). The efficiencyof the conjugation of DFO*-X (X = mal, PODS, VK) to HSA differed significantly,with mal &gt; PODS &gt; VK. Stability studies of the ⁸⁹Zr-labeledHSA-conjugates indicated good stability for [⁸⁹Zr]Zr-DFO*malHSA <strong>11</strong> and [⁸⁹Zr]Zr-DFO*-POD-HSA <strong>12</strong> inblood serum but only the latter was found stable in cell culture medium.[⁸⁹Zr]Zr-DFO*VK-HSA <strong>13</strong> was excluded from biologicalexperiments due to its surprisingly low stability in all media tested.[⁸⁹Zr]Zr-DFO*-POD-HSA <strong>12</strong> was further investigatedin CT26-tumor-bearing mice by PET/CT imaging and biodistribution studies.Specific uptake of radioactivity in tumors was high (up to 17% ID/g)and the tumors could be clearly visualized by PET at all time pointswith excellent tumor-to-background signal (tumor-to-blood ratio 3.2± 1.0 after 48 h p.i.). Unexpectedly, the uptake of radioactivityin bones was observed for [⁸⁹Zr]Zr-DFO*-POD-HSA <strong>12</strong>. Overall, the in vivo performance of [⁸⁹Zr]Zr-DFO*-labeledHSA obtained by mal chemistry is the most promising candidate as acompanion diagnostic PET imaging probe for the stratification of patientsfor therapies based on HSA-binding (pro-)drugs.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 3","pages":"282–292"},"PeriodicalIF":3.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148296769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MAPK Pathway Inhibition Reshapes Kinase Chemical Probe Reactivity Reflecting Cellular Activation States","authors":"Andrew F. Jarvis,&nbsp;Mohd Younis Bhat,&nbsp;Timothé Maujean,&nbsp;Ahlenne L. Abreu,&nbsp;Kaitlyn Toy,&nbsp;George M. Burslem,&nbsp;Donita C. Brady","doi":"10.1021/acsbiomedchemau.5c00231","DOIUrl":"10.1021/acsbiomedchemau.5c00231","url":null,"abstract":"<p>Despite the pivotal role of oncogenic kinases in cancerinitiation,progression, and therapeutic resistance, functionally profiling theiractivity and conformational dynamics in live cells remains challenging.Existing methods often fail to capture inhibitor-bound structuralstates of kinases, particularly in clinically relevant contexts, suchas treatment response and acquired resistance, where genomic dataalone are insufficient. Here, we use activity-based protein profiling(ABPP) to monitor composite amino acid reactivity changes, acrosscysteine, lysine, and carboxylic acid residues, as a hypothesis-generatingreadout of kinase state in live cells. Using electrophilic probes,we show that treatment of BRAFV600E mutant melanoma cells with vemurafenibor trametinib decreases overall cysteine and lysine reactivity inBRAFV600E and MEK1/2, likely reflecting composite changes in aminoacid accessibility across multiple reactive residues associated withinhibitor binding. Changing the order of probe addition and inhibitortreatment altered the labeling outcomes, consistent with competitiveengagement and structural stabilization. Comparative analysis of ATP-competitiveBRAFV600E inhibitors vemurafenib and dabrafenib indicated differencesin aspartate and glutamate labeling patterns, consistent with thepossibility that ABPP may detect inhibitor-associated variations inresidue accessibility, which could reflect differences in inhibitor-boundconformations. In inhibitor-resistant melanoma models, ABPP detecteddifferences in residue reactivity relative to parental cells, whichaligned with known resistance-associated features, such as BRAF overexpressionand the MEK2 Q60P activation mutation. Moreover, global proteome analysesof cysteine and lysine reactivity upon BRAFV600E inhibition revealedprobe-accessible cysteine labeling changes on KSR2, suggesting a potentialMAPK pathway remodeling. Together, these findings highlight ABPP asa valuable chemical biology approach for investigating inhibitor-dependentchanges in kinase residue reactivity, offering a framework to investigatehow kinase conformational dynamics and signaling pathway adaptationinfluence the therapeutic response and resistance in cancer.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 2","pages":"178–191"},"PeriodicalIF":3.5,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147723824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fine-Tuning a Transformer Model for METTL3 Lead Optimization","authors":"Christian M. Matter,&nbsp;Amedeo Caflisch","doi":"10.1021/acsbiomedchemau.5c00198","DOIUrl":"10.1021/acsbiomedchemau.5c00198","url":null,"abstract":"<p>Transformers aremachine learning models originally developedtotranslate between natural languages. Recently, a transformer modelwas trained on knowledge of medicinal chemistry, i.e., matched molecularpairs of nearly a million bioactive compounds from the ChEMBL database.Here, we customize (i.e., fine-tune) the pretrained model to enhancethe affinity and/or metabolic stability of a series of inhibitorsof methyltransferase-like protein 3 (METTL3). We first fine-tune thetransformer model using a data set of about 500 METTL3 inhibitorswith known binding affinities and validate it by retrospective analysis.Then, we fine-tune the original transformer model to simultaneouslyoptimize binding affinity and metabolic stability in a prospectiveapplication. Two of the five METTL3 inhibitors predicted by the multiobjectiveoptimized model show low-nanomolar potency and higher stability thanthe lead compound of the chemical series used for fine-tuning.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 2","pages":"160–167"},"PeriodicalIF":3.5,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147723818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pyrazolylpyrimidinamines Decorated via Petasis Reaction as Small-Molecule Activators of the RNA-Degrading Ribonuclease IRE1α","authors":"Amrutha K. Avathan Veettil,&nbsp;Yang Liu,&nbsp;Leon Wagner,&nbsp;Oguz Hastürk,&nbsp;Nguyen Song Thu Huynh,&nbsp;Giorgia Mancino,&nbsp;Maria Beerbaum,&nbsp;Peng Wu","doi":"10.1021/acsbiomedchemau.5c00161","DOIUrl":"10.1021/acsbiomedchemau.5c00161","url":null,"abstract":"<p>The multicomponent Petasis boron-Mannich reaction (PR)enablesthe generation of functionalized amines that are of biological interest.Here, we demonstrated that a series of pyrazolylpyrimidinamines decoratedvia PR are new small-molecule activators of the dual kinase and ribonucleaseRNA-degrading protein inositol-requiring enzyme 1α (IRE1α),which is an essential effector in the unfolded protein response associatedwith many human diseases. Compound SH4 was identified via a FRET assayand showed potent activity in activating the IRE1α ribonuclease(RNase) activity, inducing increased <em>XBP1</em> mRNA splicing,and inducing <em>Bloc1s1</em> mRNA degradation. Based on abinding mode analysis, the following series of PR-decorated functionalizedamines was further probed as IRE1α RNase activators. One PR-derivedcompound, AK177, showed nanomolar activating potency in biochemicalassays but minimal activities in cellular evaluations. Overall, wepresent here a series of pyrazolylpyrimidinamines as new small-moleculeactivators of the IRE1α RNase activity, which served as thefirst examples of applying PR in accessing bioactive compounds targetingthe kinase domain of a ribonuclease involved in mRNA cleavage andsplicing.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 2","pages":"118–129"},"PeriodicalIF":3.5,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147723810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of N‑Acylhydrazone Derivatives as ROCK Inhibitors: A Journey from Virtual Screening and Structure-Based De Novo Design to the Identification of ROCK2 Selective Inhibitors and Beyond","authors":"Pedro de Sena Murteira Pinheiro,&nbsp;Lucas Silva Franco,&nbsp;Raysa Magali Pillpe-Meza,&nbsp;Bárbara da Silva Mascarenhas de Jesus,&nbsp;Gabrielli Ayumi Ito Martins,&nbsp;Wesley Leandro Gouveia,&nbsp;Daniel Alencar Rodrigues,&nbsp;Marina Amaral Alves,&nbsp;Lídia Moreira Lima","doi":"10.1021/acsbiomedchemau.5c00246","DOIUrl":"10.1021/acsbiomedchemau.5c00246","url":null,"abstract":"<p>Rho-associated coiled-coil containing kinases (ROCK1and ROCK2)are central regulators of actin cytoskeleton organization and cellcontractility under physiological conditions. Dysregulation of ROCKsignaling contributes to aberrant cell migration, invasion, and tissueremodeling, positioning these kinases as attractive therapeutic targetsin cancer and fibrotic diseases. In this work, we report the discoveryof <em>N</em>-acylhydrazone (NAH) derivatives as potent andselective ROCK inhibitors, integrating structure-based virtual screening(SBVS), de novo design, and biological evaluation. Initial hit identificationfrom the LASSBio Chemical Library revealed three inhibitors (LASSBio-1828(<strong>1</strong>), LASSBio-1829 (<strong>2</strong>), and LASSBio-1919(<strong>3</strong>)), which guided the rational design of a virtual libraryof 321 NAH analogues. Docking-based prioritization, synthesis, andSAR exploration yielded compounds with low nanomolar potency, amongwhich LASSBio-2360 (<strong>12</strong>), LASSBio-2380 (<strong>17</strong>), and LASSBio-2382 (<strong>18</strong>) exhibited dual ROCK1/2 inhibition(IC₅₀ values in the 1–15 nM range), while LASSBio-2389(<strong>21</strong>) showed remarkable ROCK2 selectivity (IC₅₀ = 0.051 μM; 21-fold vs ROCK1 - IC₅₀ = 1.143 μM)and minimal inhibition of other related kinases at 500 nM. Moleculardynamics simulations demonstrated that <strong>21</strong> stabilizesthe DFG-out conformation of ROCK2, providing a structural rationalefor isoform selectivity. In vitro studies using MDA-MB-231 triple-negativebreast cancer cells confirmed that compounds <strong>12</strong>, <strong>17</strong>, <strong>18</strong>, and <strong>21</strong> inhibit migrationmore effectively than fasudil and comparably to belumosudil. Altogether,this work identifies NAH as a privileged scaffold for ROCK inhibition,delineates the molecular determinants of ROCK2 selectivity, and highlightsnew chemical leads for the development of antimetastatic and antifibroticagents targeting the Rho/ROCK pathway.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 2","pages":"192–209"},"PeriodicalIF":3.5,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147723846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of Small-Molecule Antagonists of PHF1 and 19 Demonstrates the Ligandability of PRC2 Accessory Proteins","authors":"Isabelle E. Amick,&nbsp;Rebecca L. Johnson,&nbsp;Jiuyang Liu,&nbsp;Cameron R. Bussey-Sutton,&nbsp;Ikeer Y. Mancera-Ortiz,&nbsp;Jacqueline L. Norris-Drouin,&nbsp;Shelton R. Boyd,&nbsp;Stephanie H. Cholensky,&nbsp;Cathy J. Spangler,&nbsp;Robert K. McGinty,&nbsp;Brian D. Strahl,&nbsp;Tatiana G. Kutateladze,&nbsp;Stephen V. Frye,&nbsp;Lindsey I. James","doi":"10.1021/acsbiomedchemau.5c00150","DOIUrl":"10.1021/acsbiomedchemau.5c00150","url":null,"abstract":"<p>PHF1 and PHF19 are key accessory components of polycombrepressivecomplex 2 (PRC2) which is responsible for trimethylation at histoneH3 lysine 27, ultimately leading to gene repression. PHF1 and 19 areknown for their methyl-lysine reader Tudor domains that recognizemethylated lysine 36 on H3, and they have also been implicated asdrivers of a range of cancers, including multiple myeloma. Here, wedescribe the first small-molecule antagonist of the Tudor domainsof PHF1 and 19. We screened an internal library of ∼ 1 K compoundsagainst the Tudor domains using a TR-FRET assay. Upon validation ofa hit compound, we performed structure–activity relationship(SAR) studies to better understand the binding mode and improve theaffinity of the compound for the PHF1 and 19 Tudor domains. One suchcompound, UNC7242, which binds PHF1 with a <em>K</em>_d of 1.13 ± 0.04 μM and PHF19 with a <em>K</em>_d of 0.64 ± 0.14 μM, emerged as a lead compound.UNC7242 clearly demonstrates the ligandability of these disease-relevantproteins and serves as a starting point for the future developmentof potent and selective PHF1 and 19 chemical probes.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 2","pages":"101–117"},"PeriodicalIF":3.5,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147723815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High Drug Encapsulation Capacity in Cyclodextrin-Based Nanoparticles: Characterization and In Vivo Antitumor Efficacy in Tumor-Bearing Mice","authors":"Tomoki Kosugi,&nbsp;Mina Sakuragi,&nbsp;Madoka Toya,&nbsp;Tomoki Nishimura,&nbsp;Taiki Saito,&nbsp;Reina Kobayashi,&nbsp;Liliana de Campo,&nbsp;Kazuo Sakurai,&nbsp;Riku Kawasaki,&nbsp;Noriko Miyamoto","doi":"10.1021/acsbiomedchemau.5c00220","DOIUrl":"10.1021/acsbiomedchemau.5c00220","url":null,"abstract":"<p>Insufficient drug encapsulation, typically at about 10wt %, remainsa major challenge in the design of nanotechnology-based drug deliverysystems. In this study, we created cyclodextrin-based nanoparticles(CDNP_PEGs), synthesized by the hyperbranched polymerization of cyclodextrinsusing a diepoxy poly­(ethylene glycol) linker, which exhibited a highdrug encapsulation capacity of up to 54 wt % using the xanthone derivativeα-mangostin (MGS) as a model compound. Evaluation in a tumor-bearingmouse model indicated that a single intravenous administration viathe tail vein induced a significantly greater antitumor effect comparedwith free MGS. These results demonstrate the potential of CDNP_PEGsas promising high-capacity carriers for the delivery of anticancerdrugs.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 2","pages":"168–177"},"PeriodicalIF":3.5,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147723764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CryoEM Structures of Native Quinol-Dependent Nitric Oxide Reductase in Resting and Quinol-Bound States","authors":"Faisal T. Khaja,&nbsp;Allegra Mboukou,&nbsp;Louie P. Aspinall,&nbsp;Charlotte E. Hawksworth,&nbsp;Robert R. Eady,&nbsp;Svetlana V. Antonyuk,&nbsp;Stephen P. Muench,&nbsp;S. Samar Hasnain","doi":"10.1021/acsbiomedchemau.5c00245","DOIUrl":"10.1021/acsbiomedchemau.5c00245","url":null,"abstract":"<p>The membrane-bound quinol-dependent nitric oxide reductases(qNORs),which are members of the respiratory heme-copper oxidase superfamily,are of major importance to food production, environment, and humanhealth. They are unique to bacteria and catalyze N–N bond formation,converting nitric oxide (NO) to generate the enzymatic product, nitrousoxide (N₂O), in agricultural and pathogenic conditions.High-resolution qNOR structures have been reported from two bacterialspecies, in which the molecular size of the protein was increasedby the insertion of apocytochrome b₅₆₂ (BRIL) at the C-terminusto facilitate cryoEM structure determination. However, it remainsuncertain how BRIL fusion alters the native structure of these metalloenzymes.Here, we present the first high-resolution structure of <em>Achromobacter xylosoxidans</em> qNOR (<em>Ax</em>qNOR) determined without a fusion tag at two different pH values,revealing structural differences near the catalytic core as well asoverall conformational changes between the native and fusion-taggedstructures. The native enzyme shows a bell-shaped pH dependence ofenzymatic activity, like nitrite reductase, the preceding enzyme inthe denitrification pathway, which generates the substrate NO. Inaddition, we report structures of <em>Ax</em>qNOR bound toquinol and hydroxyquinol that provide valuable insight into the potentialelectron transfer pathway originating from Trp718 to the redox centers.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 2","pages":"145–159"},"PeriodicalIF":3.5,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147723758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ligand-Induced Opening of a Cryptic Pocket in METTL14","authors":"Ivan Corbeski,&nbsp;Rajiv Kumar Bedi,&nbsp;Christian M. Matter,&nbsp;Fiona Stamm,&nbsp;Elena Bochenkova,&nbsp;Marcin Herok,&nbsp;Michael J. Hartshorn,&nbsp;Amedeo Caflisch","doi":"10.1021/acsbiomedchemau.5c00184","DOIUrl":"10.1021/acsbiomedchemau.5c00184","url":null,"abstract":"<p>The complex of methyltransferase-like proteins 3 and14 (METTL3–14)is the main human enzyme that deposits the most abundant internalmRNA modification, N⁶-methyladenosine (m⁶A).In the heterodimeric complex, METTL3 acts as a catalytic subunit whileMETTL14 is involved in mRNA binding and complex stabilization. Here,we present the discovery of small-molecule ligands that bind to acryptic pocket in METTL14 by protein crystallography. A comparativeanalysis of crystal structures revealed that the METTL14 cryptic pocketis closed in the apo structure of METTL3–14, and in the structuresof METTL3–14 in the complex with the cosubstrate <em>S</em>-adenosyl-methionine (SAM) and a large number of SAM-competitiveinhibitors. We first discovered compounds <strong>1</strong> and <strong>2</strong> that bind to both the SAM pocket in METTL3 and the crypticpocket in METTL14. With this structural information, we designed compound <strong>3</strong> that binds only to the METTL14 cryptic pocket. Compound <strong>3</strong> does not inhibit the catalytic activity of METTL3–14but can be used as an anchor for heterobifunctional molecules. Wepropose a route for its further development into heterobifunctionalligands, e.g., proteolysis targeting chimeras (PROTACs).</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 2","pages":"130–144"},"PeriodicalIF":3.5,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147723842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimization of Indole- and Pyrazole-fused Glycyrrhetinic Acid Derivatives as Potent PTP1B Inhibitors: In Silico, In Vitro, In Vivo, and Metabolomic Studies","authors":"Mitzi López-Sánchez,&nbsp;Hannya Mendoza-Mota,&nbsp;Ledy De-la-Cruz-Martínez,&nbsp;Félix Matadamas-Martínez,&nbsp;Diana Laura Torres-Chacón,&nbsp;Rosendo Martínez-Arellano,&nbsp;Juan Francisco Palacios-Espinosa,&nbsp;Jaime Pérez-Villanueva,&nbsp;Martin González-Andrade,&nbsp;José Carlos Páez-Franco,&nbsp;Julio César Almanza-Pérez,&nbsp;Francisco Cortés-Benítez","doi":"10.1021/acsbiomedchemau.5c00164","DOIUrl":"10.1021/acsbiomedchemau.5c00164","url":null,"abstract":"<p>Protein tyrosine phosphatase 1B (PTP1B) is a crucialenzyme involvedin regulating insulin and leptin signaling pathways, making it a promisingtarget for treating type 2 diabetes. In this study, we synthesized14 derivatives of indole- and pyrazole-fused glycyrrhetinic acid (GA)and evaluated their effects on PTP1B, using both its long (<em>h</em>PTP1B_1–400) and short (<em>h</em>PTP1B_1–285) forms. We analyzed enzymatic kineticsand selectivity over T-cell protein tyrosine phosphatase (TCPTP).Molecular docking and molecular dynamics simulations were performedto understand the binding mode of the compounds within PTP1B. Untargetedmetabolomics, using gas chromatography–mass spectrometry, assessedmetabolic changes caused by the most potent PTP1B inhibitors in HepG2cells. We also evaluated these inhibitors <em>in vivo</em> to determine their effects on insulin sensitivity through the insulintolerance test (ITT) in streptozotocin (STZ)-induced diabetic mice.Two compounds, <strong>4b</strong> (indole-fused) and <strong>5g</strong> (pyrazole-fused),showed greater potency against the long form of PTP1B compared tothe short form, indicating that both compounds preferentially bindto the disordered C-terminal region of PTP1B. Molecular docking andmolecular dynamics studies supported this finding. Furthermore, enzymatickinetics revealed that compounds <strong>4b</strong> and <strong>5g</strong> function as uncompetitive inhibitors of PTP1B, with <em>K</em>_i values of 0.32 and 0.72 μM, respectively. Notably,both GA derivatives exhibited more pronounced inhibition of PTP1Bcompared to the well-established inhibitors ursolic acid and Ertiprotafib,while also demonstrating selectivity over TCPTP. Metabolomic analysisrevealed that these compounds increased pantothenic acid and glycinelevels, while decreasing glucose and fatty acid levels in HepG2 cells,suggesting enhanced glycolysis and reduced lipogenesis. Both compoundsexhibited low cytotoxicity in HFF-1 cells and significantly reducedglucose levels in the ITT in STZ-induced diabetic mice, outperformingthe insulin-sensitizing drug Pioglitazone.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 1","pages":"15–35"},"PeriodicalIF":3.5,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147272143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}