Rational development of selective Inhibitors of the protein kinase DYRK1B
Final Report Abstract
In certain tumors, the protein kinase DYRK1B promotes the entry of cancer cells into a dormant phase with increased resistance to cytostatic drugs and is therefore an interesting drug target in cancer therapy. The aim of the project was therefore to develop a selective agent that would exploit the lower conformational stability of DYRK1B compared to DYRK1A in order to selectively reduce cellular DYRK1B levels. On the one hand, potential type II inhibitors were envisaged that would inhibit the tyrosine kinase activity and thus the initial folding of the catalytic domain of DYRK1B. On the other hand, chimeric compounds were to be developed in which an ATP-competitive DYRK ligand is linked to a hydrophobic part of the molecule. By increasing the hydrophobic surface area, the degradation of the kinase via the ubiquitinproteasome system was to be induced. The basic aim of this project was to explore the strategy of utilizing differences in the thermodynamic stability of closely related target proteins as a basis for drug selectivity. In the course of the project, the concept was extended to the development of PROTACs, in which the proteolysis of the target kinase was to be achieved by attached E3 ubiquitin ligands. In order to develop chemically and pharmacologically original structures, 7-haloindole-3- carbonitriles were incorporated as head groups, which had been identified in previous studies as ligands of the ATP-binding pocket of DYRK kinases. The biochemical characterization of the new compounds was carried out in cell-based assays to determine the DYRK1B concentration, whereby the selectivity towards DYRK1A was also investigated in each case. The selection of the attachment sites of linker chains to the head group was based on computational chemistry studies. The synthesis of the planned functionalized compounds was more challenging than originally planned, as a number of standard reactions could not be applied to special production steps. Nevertheless, by systematically developing alternative synthesis routes, useful test compounds were produced, chemically characterized and made available for testing. However, their biological evaluation revealed only a weak influence on the DYRK1B protein levels with low selectivity. The reason for these modest results is assumed to be that either the predicted attachment sites to the head group were unsuitable or the type and length of the linkers had not yet been optimally selected.
Publications
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[b]-Annulated Halogen-Substituted Indoles as Potential DYRK1A Inhibitors. Molecules, 24(22), 4090.
Lechner, Christian; Flaßhoff, Maren; Falke, Hannes; Preu, Lutz; Loaëc, Nadége; Meijer, Laurent; Knapp, Stefan; Chaikuad, Apirat & Kunick, Conrad
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A novel synthesis of indole-2-carbaldehydes as building blocks for biologically active compounds (Poster). 8th edition of the EFMC International Symposium on Advances in Synthetic and Medicinal Chemistry, Athen, 01.09. – 05.09.2019
Flaßhoff, M. & Kunick, C.
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7-Halogenated indoles as potential DYRK1A/B degraders (Poster)., ACS Fall Meeting 2022, Chicago, Illinois, USA, 21.08. – 25.08.2022
Flaßhoff, M., Wilms, G., Bordi, S., Wanner, B., Becker, W. & Kunick, C.
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Differential maturation and chaperone dependence of the paralogous protein kinases DYRK1A and DYRK1B. Scientific Reports, 12(1).
Papenfuss, Marco; Lützow, Svenja; Wilms, Gerrit; Babendreyer, Aaron; Flaßhoff, Maren; Kunick, Conrad & Becker, Walter
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Discovery of novel 6-hydroxybenzothiazole urea derivatives as dual Dyrk1A/α-synuclein aggregation inhibitors with neuroprotective effects. European Journal of Medicinal Chemistry, 227, 113911.
AlNajjar, Yasmeen T.; Gabr, Moustafa; ElHady, Ahmed K.; Salah, Mohamed; Wilms, Gerrit; Abadi, Ashraf H.; Becker, Walter; Abdel-Halim, Mohammad & Engel, Matthias
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Synthesis of 7-iodinated indoles as potential DYRK1A/B Degraders (Poster). 27th edition of the EFMC International Symposium on Medicinal Chemistry, Nizza, 04.09. – 08.09.2022
Flaßhoff, M. & Kunick, C.
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Synthesis of 7-iodinated indoles as potential DYRK1A/B Degraders (Poster). 9th edition of EFMC Young Medicinal Chemist’s Symposium, Nizza, 08.09. – 09.09.2022
Flaßhoff, M. & Kunick, C.
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Targeted degradation of the protein kinase DYRK1A (Vortrag), Conference “DYRK1A, related kinases and human diseases, St. Malo, Frankreich, 22.-26.11.2022
Wilms, G., Schofield, K., Hulme, C. & Becker, W.
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Targeted degradation of the protein kinase DYRK1A using PROTACs. Naunyn-Schmiedeberg's Arch Pharmacol (2023) 396 (Suppl1):S24
Wilms, G., Schofield, K., Hulme, C. & Becker, W.
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Potentielle Modulatoren der Proteinkinasen DYRK1A und DYRK1B – Design und Synthese. Dissertation Technische Universität Braunschweig
Flaßhoff M.
