Rácz, Anita and Palkó, Roberta and Csányi, Dorottya and Riedl, Zsuzsanna and Bajusz, Dávid and Keserű, György Miklós (2022) Consensus Virtual Screening Identified [1,2,4]Triazolo[1,5-b]isoquinolines As MELK Inhibitor Chemotypes. CHEMMEDCHEM, 17 (2). ISSN 1860-7179
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Abstract
Maternal Embryonic Leucine-zipper Kinase (MELK) is a current oncotarget involved in a diverse range of human cancers, with the usage of MELK inhibitors being explored clinically. Here, we aimed to discover new MELK inhibitor chemotypes from our in-house compound library with a consensus-based virtual screening workflow, employing three screening concepts. After careful retrospective validation, prospective screening and in vitro enzyme inhibition testing revealed a series of [1,2,4]triazolo[1,5-b]isoquinolines as a new structural class of MELK inhibitors, with the lead compound of the series exhibiting a sub-micromolar inhibitory activity. The structure-activity relationship of the series was explored by testing further analogs based on a structure-guided selection process. Importantly, the present work marks the first disclosure of the synthesis and bioactivity of this class of compounds. © 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH
| Item Type: | Article |
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| Additional Information: | Plasma Chemistry Research Group, Research Centre for Natural Sciences, Magyar tudósok krt. 2, Budapest, 1117, Hungary Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Magyar tudósok krt. 2, Budapest, 1117, Hungary Present affiliation: Organocatalysis Research Group, Research Centre for Natural Sciences, Magyar tudósok krt. 2, Budapest, 1117, Hungary Export Date: 3 November 2021 CODEN: CHEMG Correspondence Address: Bajusz, D.; Medicinal Chemistry Research Group, Magyar tudósok krt. 2, Hungary; email: bajusz.david@ttk.hu Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFIH Funding details: Magyar Tudományos Akadémia, MTA Funding details: Hungarian Scientific Research Fund, OTKA, PD134416 Funding details: Innovációs és Technológiai Minisztérium Funding text 1: The authors thank their colleagues at the MS Metabolomics Laboratory Core Facility at RCNS for the HRMS measurements, and Károly Héberger for helpful discussions. The work of A.R. is supported by the National Research, Development and Innovation Office of Hungary (OTKA, contract no. PD134416). The work of D.B. is supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences and the ÚNKP‐21‐5 New National Excellence Program of the Ministry for Innovation and Technology. |
| Uncontrolled Keywords: | KINASE; ISOQUINOLINE; Docking; Virtual screening; MELK inhibitor; |
| Subjects: | Q Science / természettudomány > QD Chemistry / kémia |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 13 Sep 2022 14:54 |
| Last Modified: | 13 Sep 2022 14:54 |
| URI: | http://real.mtak.hu/id/eprint/148561 |
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