TY - JOUR AU - Póti, Ádám Levente AU - Bálint, Dániel AU - Alexa, Anita AU - Sok, Péter Dániel AU - Ozsváth, Kristóf AU - Albert, Krisztián AU - Turczel, Gábor AU - Magyari, Sarolt AU - Ember, Orsolya AU - Papp, Kinga AU - Király, Sándor Balázs AU - Imre, Timea AU - Németh, Krisztina AU - Kurtán, Tibor AU - Gógl, Gergő AU - Varga, Szilárd AU - Soós, Tibor AU - Reményi, Attila TI - Targeting a key protein-protein interaction surface on mitogen-activated protein kinases by a precision-guided warhead scaffold JF - NATURE COMMUNICATIONS J2 - NAT COMMUN VL - 15 PY - 2024 IS - 1 PG - 22 SN - 2041-1723 DO - 10.1038/s41467-024-52574-1 UR - https://m2.mtmt.hu/api/publication/35435914 ID - 35435914 N1 - Biomolecular Interaction Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Budapest, Hungary Doctoral School of Biology, Eötvös Loránd University, Budapest, Hungary Organocatalysis Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Budapest, Hungary Hevesy György PhD School of Chemistry, Eötvös Loránd University, Budapest, Hungary NMR Research Laboratory, Centre for Structural Science, Research Centre for Natural Sciences, Budapest, Hungary Department of Organic Chemistry, University of Debrecen, Debrecen, Hungary MS Metabolomic Research Laboratory, Centre for Structural Science, Research Centre for Natural Sciences, Budapest, Hungary Cited By :1 Export Date: 16 January 2025 Correspondence Address: Reményi, A.; Biomolecular Interaction Research Group, Hungary; email: remenyi.attila@ttk.hu Correspondence Address: Soós, T.; Organocatalysis Research Group, Hungary; email: soos.tibor@ttk.hu AB - For mitogen-activated protein kinases (MAPKs) a shallow surface—distinct from the substrate binding pocket—called the D(ocking)-groove governs partner protein binding. Screening of broad range of Michael acceptor compounds identified a double-activated, sterically crowded cyclohexenone moiety as a promising scaffold. We show that compounds bearing this structurally complex chiral warhead are able to target the conserved MAPK D-groove cysteine via reversible covalent modification and interfere with the proteinprotein interactions of MAPKs. The electronic and steric properties of the Michael acceptor can be tailored via different substitution patterns. The inversion of the chiral center of the warhead can reroute chemical bond formation with the targeted cysteine towards the neighboring, but less nucleophilic histidine. Compounds bind to the shallow MAPK D-groove with low micromolar affinity in vitro and perturb MAPK signaling networks in the cell. This class of chiral, cyclic and enhanced 3D shaped Michael acceptor scaffolds offers an alternative to conventional ATP-competitive drugs modulating MAPK signaling pathways. LA - English DB - MTMT ER - TY - JOUR AU - Bálint, Dániel AU - Póti, Ádám Levente AU - Alexa, Anita AU - Sok, Péter Dániel AU - Albert, Krisztián AU - Torda, Lili AU - Földesi-Nagy, Dóra AU - Csókás, Dániel AU - Turczel, Gábor AU - Imre, Timea AU - Kállainé Szarka, Eszter AU - Fekete, Ferenc AU - Bento, Isabel AU - Bojtár, Márton Gáspár AU - Palkó, Roberta AU - Szabó, Pál Tamás AU - Monostory, Katalin AU - Pápai, Imre AU - Soós, Tibor AU - Reményi, Attila TI - Reversible covalent c-Jun N-terminal kinase inhibitors targeting a specific cysteine by precision-guided Michael-acceptor warheads JF - NATURE COMMUNICATIONS J2 - NAT COMMUN VL - 15 PY - 2024 IS - 1 SN - 2041-1723 DO - 10.1038/s41467-024-52573-2 UR - https://m2.mtmt.hu/api/publication/35435905 ID - 35435905 N1 - Organocatalysis Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Budapest, 1117, Hungary Hevesy György PhD School of Chemistry, Eötvös Loránd University, Budapest, 1117, Hungary Biomolecular Interaction Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Budapest, 1117, Hungary Doctoral School of Biology, Eötvös Loránd University, Budapest, 1117, Hungary Theoretical Chemistry Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Budapest, 1117, Hungary NMR Research Laboratory, Centre for Structural Science, Research Centre for Natural Sciences, Budapest, 1117, Hungary MS Metabolomic Research Laboratory, Centre for Structural Science, Research Centre for Natural Sciences, Budapest, 1117, Hungary Metabolic Drug-interactions Research Group, Institute of Molecular Life Sciences, Research Centre for Natural Sciences, Budapest, 1117, Hungary European Molecular Biology Laboratory, EMBL, Hamburg, Germany Chemical Biology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Budapest, 1117, Hungary Cited By :1 Export Date: 15 January 2025 Correspondence Address: Soós, T.; Organocatalysis Research Group, Hungary; email: soos.tibor@ttk.hu Correspondence Address: Reményi, A.; Biomolecular Interaction Research Group, Hungary; email: remenyi.attila@ttk.hu LA - English DB - MTMT ER - TY - PAT AU - Reményi, Attila AU - Soós, Tibor AU - Póti, Ádám Levente AU - Bálint, Dániel AU - Alexa, Anita AU - Sok, Péter Dániel AU - Torda, Lili AU - Varga, Szilárd AU - Ozsváth, Kristóf AU - Albert, Krisztián AU - Palkó, Roberta AU - Ember, Orsolya AU - Kállainé Szarka, Eszter AU - Imre, Timea TI - Cyclic designer scaffolds for the covalent targeting of proteins via michael addition PY - 2024 UR - https://m2.mtmt.hu/api/publication/35161458 ID - 35161458 AB - Many biologically active natural products contain electrophilic Michael acceptor fragments. For example, curcumin and 4-hydroxyderricin contain an acyclic α,β-unsaturated ketone that alkylates cysteines. Other antitumor or anti-inflammatory herbal compounds such as Withaferin A or zerumbone contain cyclic α,β-unsaturated ketones and react with nucleophilic residues of proteins. These observations contributed to a paradigm shift in drug design and development in the last two decades: various drugs with covalent warhead have been developed and approved. Despite the apparent importance and success of covalent warheads in current drug design and developments, the applied warheads display a rather limited structural variance and complexity which automatically limits the attainable chemical space. Furthermore, to minimize possible side-reactions during the synthesis of drugs, the applied warheads are added appendages in the late-stage of the synthetic route, thus a warhead scaffold that can be synthetically easily varied using orthogonal chemistry and used as a tunable covalent warhead is still missing. Such a structurally more complex scaffold would be much more like the warheads of the natural products and is expected to be more selective in targeting nucleophiles found on the proteins. Moreover, owing to a larger contact surface, it might be more suitable for targeting shallow protein surfaces involved in protein-protein interactions. LA - English DB - MTMT ER -