TY - JOUR AU - Bajusz, Dávid AU - Keserű, György Miklós TI - Maximizing the integration of virtual and experimental screening in hit discovery JF - EXPERT OPINION ON DRUG DISCOVERY J2 - EXPERT OPIN DRUG DIS VL - 17 PY - 2022 IS - 6 SP - 629 EP - 640 PG - 12 SN - 1746-0441 DO - 10.1080/17460441.2022.2085685 UR - https://m2.mtmt.hu/api/publication/32869275 ID - 32869275 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 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 - de Araujo, Elvin D. AU - Keserű, György Miklós AU - Gunning, Patrick T. AU - Moriggl, Richard TI - Targeting STAT3 and STAT5 in Cancer JF - CANCERS J2 - CANCERS VL - 12 PY - 2020 IS - 8 PG - 8 SN - 2072-6694 DO - 10.3390/cancers12082002 UR - https://m2.mtmt.hu/api/publication/31699647 ID - 31699647 LA - English DB - MTMT ER - TY - JOUR AU - Karancsiné Menyhárd, Dóra AU - Pálfy, Gyula AU - Orgován, Zoltán AU - Vida, István AU - Keserű, György Miklós AU - Perczel, András TI - Structural impact of GTP binding on downstream KRAS signaling JF - CHEMICAL SCIENCE J2 - CHEM SCI VL - 11 PY - 2020 IS - 34 SP - 9272 EP - 9289 PG - 18 SN - 2041-6520 DO - 10.1039/d0sc03441j UR - https://m2.mtmt.hu/api/publication/31605838 ID - 31605838 N1 - Funding Agency and Grant Number: National Research, Development and Innovation Office of Hungary [NVKP_16-1-2016-0020, OTKA K116904, OTKA K116305]; Hungarian Ministry of Human Capacities; European Regional Development FundEuropean Union (EU) [VEKOP-2.3.2-16-2017-00014]; HunProtEx Funding text: The National Research, Development and Innovation Office of Hungary (grant numbers: NVKP_16-1-2016-0020, OTKA K116904, and OTKA K116305) and the Hungarian Ministry of Human Capacities and co-financed by the European Regional Development Fund (VEKOP-2.3.2-16-2017-00014) and HunProtEx. Funding Agency and Grant Number: National Research, Development and Innovation Office of Hungary [NVKP_16-1-2016-0020, OTKA K116904, OTKA K116305]; Hungarian Ministry of Human Capacities; European Regional Development FundEuropean Commission [VEKOP-2.3.2-16-2017-00014]; HunProtEx Funding text: The National Research, Development and Innovation Office of Hungary (grant numbers: NVKP_16-1-2016-0020, OTKA K116904, and OTKA K116305) and the Hungarian Ministry of Human Capacities and co-financed by the European Regional Development Fund (VEKOP-2.3.2-16-2017-00014) and HunProtEx. AB - Oncogenic RAS proteins, involved in similar to 30% of human tumors, are molecular switches of various signal transduction pathways. Here we apply a new protocol for the NMR study of KRAS in its (inactive) GDP- and (activated) GTP-bound form, allowing a comprehensive analysis of the backbone dynamics of its WT-, G12C- and G12D variants. We found that Tyr32 shows opposite mobility with respect to the backbone of its surroundings: it is more flexible in the GDP-bound form while more rigid in GTP-complexes (especially in WT- and G12D-GTP). Using the G12C/Y32F double mutant, we showed that the presence of the hydroxyl group of Tyr32 has a marked effect on the G12C-KRAS-GTP system as well. Molecular dynamics simulations indicate that Tyr32 is linked to the gamma-phosphate of GTP in the activated states - an arrangement shown, using QM/MM calculations, to support catalysis. Anchoring Tyr32 to the gamma-phosphate contributes to the capture of the catalytic waters participating in the intrinsic hydrolysis of GTP and supports a simultaneous triple proton transfer step (catalytic water -> assisting water -> Tyr32 -> O1G of the gamma-phosphate) leading to straightforward product formation. The coupled flip of negatively charged residues of switch I toward the inside of the effector binding pocket potentiates ligand recognition, while positioning of Thr35 to enter the coordination sphere of the Mg(2+)widens the pocket. Position 12 mutations do not disturb the capture of Tyr32 by the gamma-phosphate, but (partially) displace Gln61, which opens up the catalytic pocket and destabilizes catalytic water molecules thus impairing intrinsic hydrolysis. LA - English DB - MTMT ER - TY - JOUR AU - Orgován, Zoltán AU - Keserű, György Miklós TI - Small molecule inhibitors of RAS proteins with oncogenic mutations JF - CANCER AND METASTASIS REVIEWS J2 - CANCER METAST REV VL - 39 PY - 2020 SP - 1107 EP - 1126 PG - 20 SN - 0167-7659 DO - 10.1007/s10555-020-09911-9 UR - https://m2.mtmt.hu/api/publication/31473660 ID - 31473660 N1 - Export Date: 28 August 2020 CODEN: CMRED Correspondence Address: Keserű, G.M.; Medicinal Chemistry Research Group, Research Centre for Natural Sciences, 2 Magyar tudósok körútja, Hungary; email: gy.keseru@ttk.mta.hu Funding details: NVKP_16-1-2016-0020 Funding text 1: This work has been supported by the National Research, Development and Innovation Office under the contract number NVKP_16-1-2016-0020. Open access funding provided by ELKH Research Centre for Natural Sciences. AB - RAS proteins control a number of essential cellular processes as molecular switches in the human body. Presumably due to their important signalling role, RAS proteins are among the most frequently mutated oncogenes in human cancers. Hence, numerous efforts were done to develop appropriate therapies for RAS-mutant cancers in the last three decades. This review aimed to collect all of the reported small molecules that affect RAS signalling. These molecules can be divided in four main branches. First, we address approaches blocking RAS membrane association. Second, we focus on the stabilization efforts of non-productive RAS complexes. Third, we examine the approach to block RAS downstream signalling through disturbance of RAS-effector complex formation. Finally, we discuss direct inhibition; particularly the most recently reported covalent inhibitors, which are already advanced to human clinical trials. © 2020, The Author(s). LA - English DB - MTMT ER - TY - JOUR AU - de Araujo, Elvin D. AU - Orlova, Anna AU - Neubauer, Heidi A. AU - Bajusz, Dávid AU - Seo, Hyuk-Soo AU - Dhe-Paganon, Sirano AU - Keserű, György Miklós AU - Moriggl, Richard AU - Gunning, Patrick T. TI - Structural Implications of STAT3 and STAT5 SH2 Domain Mutations JF - CANCERS J2 - CANCERS VL - 11 PY - 2019 IS - 11 SN - 2072-6694 DO - 10.3390/cancers11111757 UR - https://m2.mtmt.hu/api/publication/30939226 ID - 30939226 LA - English DB - MTMT ER - TY - JOUR AU - Orlova, Anna AU - Wagner, Christina AU - de Araujo, Elvin D. AU - Bajusz, Dávid AU - Neubauer, Heidi A. AU - Herling, Marco AU - Gunning, Patrick T. AU - Keserű, György Miklós AU - Moriggl, Richard TI - Direct Targeting Options for STAT3 and STAT5 in Cancer JF - CANCERS J2 - CANCERS VL - 11 PY - 2019 IS - 12 SP - 1930 SN - 2072-6694 DO - 10.3390/cancers11121930 UR - https://m2.mtmt.hu/api/publication/31011700 ID - 31011700 LA - English DB - MTMT ER - TY - JOUR AU - Orlova, Anna AU - Wingelhofer, Bettina AU - Neubauer, Heidi A AU - Maurer, Barbara AU - Berger-Becvar, Angelika AU - Keserű, György Miklós AU - Gunning, Patrick T AU - Valent, Peter AU - Moriggl, Richard TI - Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas JF - EXPERT OPINION ON THERAPEUTIC TARGETS J2 - EXPERT OPIN THER TARG VL - 22 PY - 2018 IS - 1 SP - 45 EP - 57 PG - 13 SN - 1472-8222 DO - 10.1080/14728222.2018.1406924 UR - https://m2.mtmt.hu/api/publication/3333557 ID - 3333557 LA - English DB - MTMT ER - TY - JOUR AU - Wingelhofer, Bettina AU - Maurer, Barbara AU - Heyes, Elizabeth C AU - Cumaraswamy, Abbarna C AU - Berger-Becvar, Angelika AU - de Araujo, Elvin D AU - Orlova, Anna AU - Freund, Patricia AU - Ruge, Frank AU - Park, Jisung AU - Tin, Gary AU - Ahmar, Siawash AU - Lardeau, Charles-Hugues AU - Sadovnik, Irina AU - Bajusz, Dávid AU - Keserű, György Miklós AU - Grebien, Florian AU - Kubicek, Stefan AU - Valent, Peter AU - Gunning, Patrick T AU - Moriggl, Richard TI - Pharmacologic inhibition of STAT5 in acute myeloid leukemia JF - LEUKEMIA J2 - LEUKEMIA VL - 32 ET - 0 PY - 2018 IS - 5 SP - 1135 EP - 1146 PG - 12 SN - 0887-6924 DO - 10.1038/s41375-017-0005-9 UR - https://m2.mtmt.hu/api/publication/3333358 ID - 3333358 LA - English DB - MTMT ER -