TY - JOUR AU - Garami, Kristóf Noel AU - Péczka, Nikolett AU - Petri, László AU - Imre, Tímea AU - Langó, Tamás AU - Szabó, Zoltán AU - Orgován, Zoltán AU - Szabó, Pál Tamás AU - Keserű, György Miklós AU - Ábrányi-Balogh, Péter TI - Target agnostic photoaffinity labelling by sulfonylhydrazones JF - ANGEWANDTE CHEMIE-INTERNATIONAL EDITION J2 - ANGEW CHEM INT EDIT VL - 64 PY - 2025 IS - 17 PG - 7 SN - 1433-7851 DO - 10.1002/anie.202408701 UR - https://m2.mtmt.hu/api/publication/35781560 ID - 35781560 N1 - Funding Agency and Grant Number: National Research Development and Innovation Office of Hungary [OTKA K135150, 2020-1.1.6-JOEVO-2021-00004]; National Brain Research Program [NAP 3.0] of the Hungarian Academy of Sciences; New National Excellence Program of the Ministry for Innovation and Technology [UNKP-23-5]; Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences; [RRF-2.3.1-21-2022-00015]; [UNKP-22-5] Funding text: The authors received funding from the National Research Development and Innovation Office of Hungary [PharmaLab (RRF-2.3.1-21-2022-00015. OTKA K135150 and 2020-1.1.6-JOEVO-2021-00004)] and from the National Brain Research Program [NAP 3.0] of the Hungarian Academy of Sciences. The work of P.A-B. was supported by the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences and the UNKP-22-5 and UNKP-23-5 New National Excellence Program of the Ministry for Innovation and Technology. Authors gratefully acknowledge the contribution of Claudia Binda, Marton Gadanecz, Elvin D de Araujo for protein supplies, Sandor Spisak and Ivan Ran & dstrok;elovic for providing cell lines, Gabor Tusnady for his advice in proteomics, Krisztina Nemeth and Gitta Schlosser for additional MS measurements. AB - Photoaffinity labeling is a widely used methodology for interrogating small molecule-protein interactions. However, these applications are limited by the few photo-crosslinkers that typically modify the affinity and the binding mode of the original ligand. Here, we report the development of new target agnostic photoaffinity warheads, sulfohydrazones that form a reactive carbene upon UV irradiation. Careful optimization of the reaction conditions allowed us to effectively label five different amino acid residues in proteins. Our approach turned biologically relevant hydrazones and sulfohydrazones to intrinsically irreversible covalent binders without structural modifications by photoactivation as demonstrated on monoamine oxidase A (MAO-A) enzyme and STAT5b (Signal transducer and activator of transcription 5b) transcription factor. Sulfohydrazones are readily accessible by transforming the corresponding carbonyl group of a ligand or a suitable tag that extends the application domain of the method for any ligands exemplified by conditional labelling of the acetylcholine esterase enzyme and the oncogenic mutant of GTP-ase KRasG12D. © 2025 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH. LA - English DB - MTMT ER - TY - THES AU - Péczka, Nikolett TI - Identification of covalent inhibitors against oncogenic protein targets PB - Budapesti Műszaki és Gazdaságtudományi Egyetem PY - 2025 UR - https://m2.mtmt.hu/api/publication/36163688 ID - 36163688 LA - English DB - MTMT ER - TY - JOUR AU - Petri, László AU - Gabizon, Ronen AU - Ferenczy, György AU - Péczka, Nikolett AU - Egyed, Attila AU - Ábrányi-Balogh, Péter AU - Takács, Tamás AU - Keserű, György Miklós TI - Size-Dependent Target Engagement of Covalent Probes JF - JOURNAL OF MEDICINAL CHEMISTRY J2 - J MED CHEM VL - 68 PY - 2025 IS - 6 SP - 6616 EP - 6632 PG - 17 SN - 0022-2623 DO - 10.1021/acs.jmedchem.5c00017 UR - https://m2.mtmt.hu/api/publication/36001331 ID - 36001331 N1 - Funding Agency and Grant Number: Nemzeti Kutat?si Fejleszt?si ?s Innov?ci?s Hivatal [RRF-2.3.1-21-2022-00015]; National Research, Development, and Innovation Office of Hungary (PharmaLab) Funding text: We are grateful to Nir London for valuable suggestions and for reviewing the manuscript. This research was funded by the National Research, Development, and Innovation Office of Hungary (PharmaLab RRF-2.3.1-21-2022-00015). AB - Labeling proteins with covalent ligands is finding increasing use in proteomics applications, including identifying nucleophilic residues amenable for labeling and in the development of targeted covalent inhibitors (TCIs). Labeling efficiency is measured by the covalent occupancy of the target or by biochemical activity. Here, we investigate how these observed quantities relate to the intrinsic parameters of complex formation, namely, noncovalent affinity and covalent reactivity, and to experimental conditions, including incubation time and ligand concentration. It is shown that target engagement is beneficially driven by noncovalent recognition for lead-like compounds, which are appropriate starting points for targeted covalent inhibitors owing to their easily detectable occupancy and fixed binding mode, facilitating optimization. In contrast, labeling by fragment-sized compounds is inevitably reactivity-driven as their small size limits noncovalent affinity. They are well-suited for exploring ligandable nucleophilic residues, while small fragments are less appropriate starting points for TCI development. LA - English DB - MTMT ER - TY - JOUR AU - Szalai, Tibor Viktor AU - Di Lorenzo, Vincenzo AU - Péczka, Nikolett AU - Mihalovits, Levente Márk AU - Petri, László AU - Ashraf, Qirat F. AU - de Araujo, Elvin D. AU - Honti, Viktor AU - Bajusz, Dávid AU - Keserű, György Miklós TI - Allosteric Covalent Inhibitors of the STAT3 Transcription Factor from Virtual Screening JF - ACS MEDICINAL CHEMISTRY LETTERS J2 - ACS MED CHEM LETT VL - 16 PY - 2025 IS - 6 SP - 991 EP - 997 PG - 7 SN - 1948-5875 DO - 10.1021/acsmedchemlett.4c00622 UR - https://m2.mtmt.hu/api/publication/36122949 ID - 36122949 N1 - The authors received funding from the MSCA ITN ‘ALLODD’ [grant no. 956314 to G.M.K.], the Ministry of Culture and Innovation of Hungary [grant no. 2020-1.1.2-PIACI-KFI-2020-00039], the National Research Development and Innovation Office of Hungary [FK146063 to D.B., K135150 and PharmaLab (RRF-2.3.1-21-2022-00015) to G.M.K.] and the Schweizerische Nationalfonds (SNF) [MAPS 230109]. The National Laboratory of Biotechnology was supported by the Hungarian National Research, Development and Innovation Office-NKFIH through grant No. 2022-2.1.1-NL-2022-00008. The work of D.B. was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. We acknowledge the HPC time and support of the Governmental Information Technology Development Agency, Hungary. AB - The STAT family of transcription factors are important signaling hubs, with several of them, particularly STAT3, being emerging oncotargets already investigated in clinical trials. The modular structure of STAT3 nominates several of its protein domains as possible drug targets, but their exploitation with potential small-molecule inhibitors has been unevenly distributed so far, with past efforts highly favoring the conserved SH2 domain. Here, we have targeted a sparsely studied binding site at the junction of the coiled-coil and DNA-binding domains and discovered several new lead-like covalent inhibitors by virtual screening. The most favorable hit compound has been explored via structure-guided hit expansion and optimized into a low micromolar inhibitor. This compound can serve as a chemical biology tool against this site in future exploratory studies or form the basis of a more advanced stage of lead optimization. © 2025 The Authors. Published by American Chemical Society. LA - English DB - MTMT ER - TY - JOUR AU - Szalai, Tibor Viktor AU - Péczka, Nikolett AU - Sipos-Szabó, Levente AU - Petri, László AU - Bajusz, Dávid AU - Keserű, György Miklós TI - Ultrahigh-Throughput Virtual Screening Strategies against PPI Targets: A Case Study of STAT Inhibitors JF - JOURNAL OF CHEMICAL INFORMATION AND MODELING J2 - J CHEM INF MODEL VL - 65 PY - 2025 IS - 14 SP - 7734 EP - 7748 PG - 15 SN - 1549-9596 DO - 10.1021/acs.jcim.5c00907 UR - https://m2.mtmt.hu/api/publication/36228040 ID - 36228040 N1 - Acknowledgments: The authors thank Elvin de Araujo and Qirat Ashraf (University of Toronto) for providing the STAT proteins for the experimental work. This work was supported by the National Research Development and Innovation Office of Hungary [contracts FK146063 to D.B., K135150 and PharmaLab (RRF-2.3.1-21-2022-00015) to G.M.K.]. The work of D.B. was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. We acknowledge the HPC time and support of the Governmental Information Technology Development Agency, Hungary. AB - In recent years, virtual screening of ultralarge (108+) libraries of synthetically accessible compounds (uHTVS) became a popular approach in hit identification. With AI-assisted virtual screening workflows, such as Deep Docking, these protocols might be feasible even without supercomputers. Yet, these methodologies have their own conceptual limitations, including the fact that physics-based docking is replaced by a cheaper deep learning (DL) step for the vast majority of compounds. In turn, the performance of this DL step will highly depend on the performance of the underlying docking model that is used to evaluate parts of the whole data set to train the DL architecture itself. Here, we evaluated the performance of the popular Deep Docking workflow on compound libraries of different sizes, against benchmark cases of classic brute-force docking approaches conducted on smaller libraries. We were especially interested in more difficult, protein-protein interaction-type oncotargets where the reliability of the underlying docking model is harder to assess. Specifically, our virtual screens have resulted in several new inhibitors of two oncogenic transcription factors, STAT3 and STAT5b. For STAT5b, in particular, we disclose the first application of virtual screening against its N-terminal domain, whose importance was recognized more recently. While the AI-based uHTVS is computationally more demanding, it can achieve exceptionally good hit rates (50.0% for STAT3). Deep Docking can also work well with a compound library containing only several million (instead of several billion) compounds, achieving a 42.9% hit rate against the SH2 domain of STAT5b, while presenting a highly economic workflow with just under 120,000 compounds actually docked. © 2025 The Authors. Published by American Chemical Society. LA - English DB - MTMT ER - TY - JOUR AU - Wéber, Edit AU - Ábrányi-Balogh, Péter AU - Nagymihály, Bence AU - Karancsiné Menyhárd, Dóra AU - Péczka, Nikolett AU - Gadanecz, Márton AU - Schlosser, Gitta (Vácziné) AU - Orgován, Zoltán AU - Bogár, Ferenc AU - Bajusz, Dávid AU - Kecskeméti, Gábor AU - Szabó, Zoltán AU - Bartus, Éva AU - Tököli, Attila AU - Tóth, Gábor K. AU - Szalai, Tibor Viktor AU - Takács, Tamás AU - de Araujo, Elvin AU - Buday, László AU - Perczel, András AU - Martinek, Tamas A. AU - Keserű, György Miklós TI - Target‐templated Construction of Functional Proteomimetics Using Photo‐foldamer Libraries JF - ANGEWANDTE CHEMIE J2 - ANGEW CHEM VL - 137 PY - 2025 IS - 2 PG - 14 SN - 0044-8249 DO - 10.1002/ange.202410435 UR - https://m2.mtmt.hu/api/publication/35427664 ID - 35427664 N1 - Utánközlés, eredeti közlemény MTMT azonosítója: 35431408 AB - Current methods for proteomimetic engineering rely on structure‐based design. Here we describe a design strategy that allows the construction of proteomimetics against challenging targets without a priori characterization of the target surface. Our approach relies on (i) a 100‐membered photoreactive foldamer library, the members of which act as local surface mimetics, and (ii) the subsequent affinity maturation of the primary hits using systems chemistry. Two surface‐oriented proteinogenic side chains drove the interactions between the short helical foldamer fragments and the proteins. Diazirine‐based photo‐crosslinking was applied to sensitively detected and localize binding even to shallow and dynamic patches on representatively difficult targets. Photo‐foldamers identified functionally relevant protein interfaces, allosteric and previously unexplored targetable regions on the surface of STAT3 and an oncogenic K‐Ras variant. Target‐templated dynamic linking of foldamer hits resulted in two orders of magnitude affinity improvement in a single step. The dimeric K‐Ras ligand mimicked protein‐like catalytic functions. The photo‐foldamer approach thus enables the highly efficient mapping of protein‐protein interaction sites and provides a viable starting point for proteomimetic ligand development without a priori structural hypotheses. LA - English DB - MTMT ER - TY - JOUR AU - Wéber, Edit AU - Ábrányi-Balogh, Péter AU - Nagymihály, Bence AU - Karancsiné Menyhárd, Dóra AU - Péczka, Nikolett AU - Gadanecz, Márton AU - Schlosser, Gitta (Vácziné) AU - Orgován, Zoltán AU - Bogár, Ferenc AU - Bajusz, Dávid AU - Kecskeméti, Gábor AU - Szabó, Zoltán AU - Bartus, Éva AU - Tököli, Attila AU - Tóth, Gábor AU - Szalai, Tibor V. AU - Takács, Tamás AU - de Araujo, Elvin AU - Buday, László AU - Perczel, András AU - Martinek, Tamás AU - Keserű, György Miklós TI - Target‐templated Construction of Functional Proteomimetics Using Photo‐foldamer Libraries JF - ANGEWANDTE CHEMIE-INTERNATIONAL EDITION J2 - ANGEW CHEM INT EDIT VL - 64 PY - 2025 IS - 2 PG - 14 SN - 1433-7851 DO - 10.1002/anie.202410435 UR - https://m2.mtmt.hu/api/publication/35431408 ID - 35431408 N1 - Utánközlése: 35427664 AB - Current methods for proteomimetic engineering rely on structure‐based design. Here we describe a design strategy that allows the construction of proteomimetics against challenging targets without a priori characterization of the target surface. Our approach relies on (i) a 100‐membered photoreactive foldamer library, the members of which act as local surface mimetics, and (ii) the subsequent affinity maturation of the primary hits using systems chemistry. Two surface‐oriented proteinogenic side chains drove the interactions between the short helical foldamer fragments and the proteins. Diazirine‐based photo‐crosslinking was applied to sensitively detected and localize binding even to shallow and dynamic patches on representatively difficult targets. Photo‐foldamers identified functionally relevant protein interfaces, allosteric and previously unexplored targetable regions on the surface of STAT3 and an oncogenic K‐Ras variant. Target‐templated dynamic linking of foldamer hits resulted in two orders of magnitude affinity improvement in a single step. The dimeric K‐Ras ligand mimicked protein‐like catalytic functions. The photo‐foldamer approach thus enables the highly efficient mapping of protein‐protein interaction sites and provides a viable starting point for proteomimetic ligand development without a priori structural hypotheses. LA - English DB - MTMT ER - TY - JOUR AU - Ábrányi-Balogh, Péter AU - Bajusz, Dávid AU - Orgován, Zoltán AU - Keeley, Aaron Brian AU - Petri, László AU - Péczka, Nikolett AU - Szalai, Tibor Viktor AU - Pálfy, Gyula AU - Gadanecz, Márton AU - Grant, Emma K. AU - Imre, Tímea AU - Takács, Tamás AU - Randelovic, Ivan AU - Baranyi, Marcell AU - Marton, András Dénes AU - Schlosser, Gitta (Vácziné) AU - Ashraf, Qirat F. AU - de Araujo, Elvin D. AU - Karancsi, Tamás AU - Buday, László AU - Tóvári, József AU - Perczel, András AU - Bush, Jacob T. AU - Keserű, György Miklós TI - Mapping protein binding sites by photoreactive fragment pharmacophores JF - COMMUNICATIONS CHEMISTRY J2 - COMMUN CHEM VL - 7 PY - 2024 IS - 1 PG - 13 SN - 2399-3669 DO - 10.1038/s42004-024-01252-w UR - https://m2.mtmt.hu/api/publication/35160281 ID - 35160281 N1 - Medicinal Chemistry Research Group, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary National Drug Research and Development Laboratory, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Budapest, Hungary Department of Inorganic and Analytical Chemistry, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Budapest, Hungary Laboratory of Structural Chemistry and Biology & amp; HUN-REN–ELTE Protein Modelling Research Group, Eötvös Loránd University, Budapest, Hungary Hevesy György PhD School of Chemistry, Eötvös Loránd University, Budapest, Hungary GlaxoSmithKline, Hertfordshire, United Kingdom MS Metabolomics Research Group, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary Signal Transduction and Functional Genomics Research Group, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary Doctoral School of Biology, Institute of Biology, ELTE Eötvös Loránd University, Budapest, Hungary National Tumor Biology Laboratory and Department of Experimental Pharmacology, National Institute of Oncology, Budapest, Hungary KINETO Lab Ltd, Budapest, Hungary Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Budapest, Hungary Department of Chemical and Environmental Process Engineering, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Budapest, Hungary Waters Research Center, Budapest, Hungary MTA-ELTE Lendület Ion Mobility Mass Spectrometry Research Group, Eötvös Loránd University, Budapest, Hungary Department of Chemical & amp; Physical Sciences, University of Toronto Mississauga, Mississauga, ON, Canada Centre for Medicinal Chemistry, University of Toronto at Mississauga, Mississauga, ON, Canada Export Date: 26 August 2024 Correspondence Address: Keserű, G.M.; Medicinal Chemistry Research Group, Hungary; email: keseru.gyorgy@ttk.hu AB - Fragment screening is a popular strategy of generating viable chemical starting points especially for challenging targets. Although fragments provide a better coverage of chemical space and they have typically higher chance of binding, their weak affinity necessitates highly sensitive biophysical assays. Here, we introduce a screening concept that combines evolutionary optimized fragment pharmacophores with the use of a photoaffinity handle that enables high hit rates by LC-MS-based detection. The sensitivity of our screening protocol was further improved by a target-conjugated photocatalyst. We have designed, synthesized, and screened 100 diazirine-tagged fragments against three benchmark and three therapeutically relevant protein targets of different tractability. Our therapeutic targets included a conventional enzyme, the first bromodomain of BRD4, a protein-protein interaction represented by the oncogenic KRas G12D protein, and the yet unliganded N -terminal domain of the STAT5B transcription factor. We have discovered several fragment hits against all three targets and identified their binding sites via enzymatic digestion, structural studies and modeling. Our results revealed that this protocol outperforms screening traditional fully functionalized and photoaffinity fragments in better exploration of the available binding sites and higher hit rates observed for even difficult targets. LA - English DB - MTMT ER - TY - JOUR AU - Péczka, Nikolett AU - Randelovic, Ivan AU - Orgován, Zoltán AU - Csorba, Noémi AU - Egyed, Attila AU - Petri, László AU - Ábrányi-Balogh, Péter AU - Gadanecz, Márton AU - Perczel, András AU - Tóvári, József AU - Schlosser, Gitta (Vácziné) AU - Takács, Tamás AU - Mihalovits, Levente Márk AU - Ferenczy, György AU - Buday, László AU - Keserű, György Miklós TI - Contribution of Noncovalent Recognition and Reactivity to the Optimization of Covalent Inhibitors : A Case Study on KRasG12C JF - ACS CHEMICAL BIOLOGY J2 - ACS CHEM BIOL VL - 19 PY - 2024 IS - 8 SP - 1743 EP - 1756 PG - 14 SN - 1554-8929 DO - 10.1021/acschembio.4c00217 UR - https://m2.mtmt.hu/api/publication/35134356 ID - 35134356 N1 - Medicinal Chemistry Research Group, National Drug Discovery and Development Laboratory, HUN-REN Research Centre for Natural Sciences, Budapest, 1117, Hungary Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Budapest, 1111, Hungary Department of Experimental Pharmacology, The National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary Protein Modeling Research Group, Laboratory of Structural Chemistry and Biology, ELTE Institute of Chemistry, Budapest, 1117, Hungary Hevesy György PhD School of Chemistry, Eötvös Loránd University, Pázmány Péter sétány. 1/A, Budapest, 1117, Hungary MTA-ELTE “Lendület”, Ion Mobility Mass Spectrometry Research Group, Budapest, 1117, Hungary HUN-REN Research Centre for Natural Sciences, Signal Transduction and Functional Genomics Research Group, Budapest, 1117, Hungary Doctoral School of Biology, Institute of Biology, ELTE Eötvös Loránd University, Budapest, 1117, Hungary Export Date: 5 August 2024 CODEN: ACBCC Correspondence Address: Keserű, G.M.; Medicinal Chemistry Research Group, Hungary; email: keseru.gyorgy@ttk.hu Funding details: Ministry of Innovation, Science and Technology, MOST Funding details: Nemzeti Kutatási, Fejlesztési és Innovaciós Alap, NKFIA Funding details: TKP2021-EGA-20, TKP2021-EGA-44 Funding details: RRF-2.3.1-21-2022-00015 Funding details: 2022-2.1.1-NL-2022-00010 Funding details: National Research, Development and Innovation Office, NVKP_16-1-2016-0020 Funding text 1: The authors gratefully acknowledge the synthetic contribution of S. Csana\\u0301dy and the MS measurement support of P. Szabo\\u0301. This work has been supported by the National Research, Development and Innovation Office under the contract numbers NVKP_16-1-2016-0020 and 2020-1.1.6-JO\\u0308VO\\u030B, as well as the Thematic Excellence Program under project \\u201CSzintPlusz\\u201D and by the National Drug Research and Development Laboratory (PharmaLab) project (RRF-2.3.1-21-2022-00015). The research was also funded by the National Laboratories Excellence program (under the National Tumor Biology Laboratory Project (2022-2.1.1-NL-2022-00010)) and the Hungarian Thematic Excellence Program (TKP2021-EGA-20, TKP2021-EGA-44). T. T. was supported by the KDP-2021 Program of the Ministry of Innovation and Technology from the source of the National Research, Development and Innovation Fund. AB - Covalent drugs might bear electrophiles to chemically modify their targets and have the potential to target previously undruggable proteins with high potency. Covalent binding of drug-size molecules includes a noncovalent recognition provided by secondary interactions and a chemical reaction leading to covalent complex formation. Optimization of their covalent mechanism of action should involve both types of interactions. Noncovalent and covalent binding steps can be characterized by an equilibrium dissociation constant (KI) and a reaction rate constant (kinact), respectively, and they are affected by both the warhead and the scaffold of the ligand. The relative contribution of these two steps was investigated on a prototypic drug target KRASG12C, an oncogenic mutant of KRAS. We used a synthetically more accessible nonchiral core derived from ARS-1620 that was equipped with four different warheads and a previously described KRAS-specific basic side chain. Combining these structural changes, we have synthesized novel covalent KRASG12C inhibitors and tested their binding and biological effect on KRASG12C by various biophysical and biochemical assays. These data allowed us to dissect the effect of scaffold and warhead on the noncovalent and covalent binding event. Our results revealed that the atropisomeric core of ARS-1620 is not indispensable for KRASG12C inhibition, the basic side chain has little effect on either binding step, and warheads affect the covalent reactivity but not the noncovalent binding. This type of analysis helps identify structural determinants of efficient covalent inhibition and may find use in the design of covalent agents. LA - English DB - MTMT ER - TY - JOUR AU - Orgován, Zoltán AU - Péczka, Nikolett AU - Petri, László AU - Ábrányi-Balogh, Péter AU - Randelovic, Ivan AU - Tóth, Szilárd AU - Szakács, Gergely AU - Nyíri, Kinga AU - Vértessy, Beáta (Grolmuszné) AU - Pálfy, Gyula AU - Vida, István AU - Perczel, András AU - Tóvári, József AU - Keserű, György Miklós TI - Covalent fragment mapping of KRasG12C revealed novel chemotypes with in vivo potency JF - EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY J2 - EUR J MED CHEM VL - 250 PY - 2023 PG - 7 SN - 0223-5234 DO - 10.1016/j.ejmech.2023.115212 UR - https://m2.mtmt.hu/api/publication/33647485 ID - 33647485 N1 - Medicinal Chemistry Research Group, Research Centre for Natural Sciences, and National Drug Discovery and Development Laboratory, Budapest, Hungary Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Budapest, Hungary KINETO Lab Ltd, Budapest, Hungary Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, Hungary Laboratory of Structural Chemistry and Biology, Eötvös Loránd University, Budapest, Hungary MTA-ELTE Protein Modelling Research Group, Eötvös Loránd University, Budapest, Hungary Department of Experimental Pharmacology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, Hungary CODEN: EJMCA Correspondence Address: Keserű, G.M.; Medicinal Chemistry Research Group, 2 Magyar tudósok kӧrútja, Hungary; email: keseru.gyorgy@ttk.hu AB - G12C mutant KRas is considered druggable by allele-specific covalent inhibitors due to the nucleophilic character of the oncogenic mutant cysteine at position 12. Discovery of these inhibitors requires the optimization of both covalent and noncovalent interactions. Here, we report covalent fragment screening of our electrophilic fragment library of diverse non-covalent scaffolds equipped with 40 different electrophilic functionalities to identify fragments as suitable starting points targeting Cys12. Screening the library against KRasG12C using Ellman's free thiol assay, followed by protein NMR and cell viability assays, resulted in two potential inhibitor chemotypes. Characterization of these scaffolds in in vitro cellular- and in vivo xenograft models revealed them as promising starting points for covalent drug discovery programs. LA - English DB - MTMT ER - TY - JOUR AU - Péczka, Nikolett AU - Orgován, Zoltán AU - Ábrányi-Balogh, Péter AU - Keserű, György Miklós TI - Electrophilic warheads in covalent drug discovery: an overview JF - EXPERT OPINION ON DRUG DISCOVERY J2 - EXPERT OPIN DRUG DIS VL - 17 PY - 2022 IS - 4 SP - 413 EP - 422 PG - 10 SN - 1746-0441 DO - 10.1080/17460441.2022.2034783 UR - https://m2.mtmt.hu/api/publication/32756662 ID - 32756662 N1 - CAplus AN 2022:310212; MEDLINE PMID: 35129005 (Journal; General Review; Article); LA - English DB - MTMT ER - TY - JOUR AU - Bagi, Péter AU - Herbay, Réka Gizella AU - Péczka, Nikolett AU - Mucsi, Zoltán AU - Timári, István AU - Keglevich, György TI - Preparation of 2-phospholene oxides by the isomerization of 3-phospholene oxides JF - BEILSTEIN JOURNAL OF ORGANIC CHEMISTRY J2 - BEILSTEIN J ORG CHEM VL - 16 PY - 2020 SP - 818 EP - 832 PG - 15 SN - 1860-5397 DO - 10.3762/bjoc.16.75 UR - https://m2.mtmt.hu/api/publication/31291784 ID - 31291784 N1 - Funding Agency and Grant Number: National Research, Development and Innovation Office -NKFIH; OTKAOrszagos Tudomanyos Kutatasi Alapprogramok (OTKA) [PD 116096, NVKP_16-1-2016-0043]; EU - European Regional Development FundEuropean Union (EU) [GINOP-2.3.2-15-2016-00008] Funding text: This work was supported by the National Research, Development and Innovation Office -NKFIH (Grant No. OTKA PD 116096 and NVKP_16-1-2016-0043). The research of I.T. was supported by the EU and co-financed by the European Regional Development Fund under the GINOP-2.3.2-15-2016-00008 project. Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Műegyetem rkp. 3., Budapest, H-1111, Hungary Femtonics Ltd., Budapest, H-1094, Hungary Department of Inorganic and Analytical Chemistry, University of Debrecen, Debrecen, H-4032, Hungary Cited By :1 Export Date: 2 March 2021 CODEN: BJOCB Correspondence Address: Bagi, P.; Department of Organic Chemistry and Technology, Műegyetem rkp. 3., Hungary; email: pbagi@mail.bme.hu Funding details: European Commission, EC Funding details: European Regional Development Fund, FEDER, GINOP-2.3.2-15-2016-00008 Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFI, NVKP_16-1-2016-0043, OTKA PD 116096 Funding details: National Research, Development and Innovation Office Funding text 1: Authors are thankful to B?la M?trav?lgyi for the fruitful conversations throughout the synthetic work and the preparation of the manuscript. This work was supported by the National Research, Development and Innovation Office - NKFIH (Grant No. OTKA PD 116096 and NVKP_16-1-2016-0043). The research of I.T. was supported by the EU and co-financed by the European Regional Development Fund under the GINOP-2.3.2-15-2016-00008 project. Funding text 2: This work was supported by the National Research, Development and Innovation Office - NKFIH (Grant No. OTKA PD 116096 and NVKP_16-1-2016-0043). The research of I.T. was supported by the EU and co-financed by the European Regional Development Fund under the GINOP-2.3.2-15-2016-00008 project. Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Műegyetem rkp. 3., Budapest, H-1111, Hungary Femtonics Ltd., Budapest, H-1094, Hungary Department of Inorganic and Analytical Chemistry, University of Debrecen, Debrecen, H-4032, Hungary Cited By :1 Export Date: 3 March 2021 CODEN: BJOCB Correspondence Address: Bagi, P.; Department of Organic Chemistry and Technology, Műegyetem rkp. 3., Hungary; email: pbagi@mail.bme.hu Funding details: European Commission, EC Funding details: European Regional Development Fund, FEDER, GINOP-2.3.2-15-2016-00008 Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFI, NVKP_16-1-2016-0043, OTKA PD 116096 Funding details: National Research, Development and Innovation Office Funding text 1: Authors are thankful to B?la M?trav?lgyi for the fruitful conversations throughout the synthetic work and the preparation of the manuscript. This work was supported by the National Research, Development and Innovation Office - NKFIH (Grant No. OTKA PD 116096 and NVKP_16-1-2016-0043). The research of I.T. was supported by the EU and co-financed by the European Regional Development Fund under the GINOP-2.3.2-15-2016-00008 project. Funding text 2: This work was supported by the National Research, Development and Innovation Office - NKFIH (Grant No. OTKA PD 116096 and NVKP_16-1-2016-0043). The research of I.T. was supported by the EU and co-financed by the European Regional Development Fund under the GINOP-2.3.2-15-2016-00008 project. Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Műegyetem rkp. 3., Budapest, H-1111, Hungary Femtonics Ltd., Budapest, H-1094, Hungary Department of Inorganic and Analytical Chemistry, University of Debrecen, Debrecen, H-4032, Hungary Cited By :1 Export Date: 19 April 2021 CODEN: BJOCB Correspondence Address: Bagi, P.; Department of Organic Chemistry and Technology, Műegyetem rkp. 3., Hungary; email: pbagi@mail.bme.hu AB - A series of 1-substituted-3-methyl-2-phospholene oxides was prepared from the corresponding 3-phospholene oxides by double bond rearrangement. The 2-phospholene oxides could be obtained by heating the 3-phospholene oxides in methanesulfonic acid, or via the formation of cyclic chlorophosphonium salts. Whereas mixtures of the 2- and 3-phospholene oxides formed, when the isomerization of 3-phospholene oxides was attempted under thermal conditions, or in the presence of a base. The mechanisms of the various double bond migration pathways were elucidated by quantum chemical calculations. LA - English DB - MTMT ER - TY - JOUR AU - Herbay, Réka Gizella AU - Péczka, Nikolett AU - Györke, Gábor AU - Bagi, Péter AU - Fogassy, Elemér AU - Keglevich, György TI - Isomerization and application of phospholene oxides JF - PHOSPHORUS SULFUR AND SILICON AND THE RELATED ELEMENTS J2 - PHOSPHOR SULFUR SIL REL ELEM VL - 194 PY - 2019 IS - 4-6 SP - 610 EP - 613 PG - 4 SN - 1042-6507 DO - 10.1080/10426507.2018.1553043 UR - https://m2.mtmt.hu/api/publication/30385211 ID - 30385211 N1 - Cited By :2 Export Date: 2 March 2021 CODEN: PSSLE Correspondence Address: Herbay, R.; Department of Organic Chemistry and Technology, Hungary; email: herbay.reka@mail.bme.hu LA - English DB - MTMT ER - TY - GEN AU - Péczka, Nikolett TI - P-Sztereogén centrumot tartalmazó foszfin-oxidok alkalmazása enantioszelektív katalitikus Wittig-reakcióban PY - 2019 UR - https://m2.mtmt.hu/api/publication/32112749 ID - 32112749 LA - Hungarian DB - MTMT ER - TY - GEN AU - Péczka, Nikolett TI - Investigation of the isomerization of 1-substituted 3-methyl-3-phospholene oxides PY - 2018 UR - https://m2.mtmt.hu/api/publication/32112809 ID - 32112809 LA - English DB - MTMT ER - TY - GEN AU - Péczka, Nikolett TI - 1-Szubsztituált-3-metil-3-foszfolén-oxidok izomerizációjának vizsgálata PY - 2017 UR - https://m2.mtmt.hu/api/publication/32112736 ID - 32112736 LA - Hungarian DB - MTMT ER -