DYRK

The Dual-specificity Tyrosine phosphorylation-Regulated Kinases (DYRKs) just came recently into focus of the research. It is a family of five kinases, which are involved in proliferation and differentiation. The DYRK1A gene is located in the Down syndrome critical region and its regulative role in cellular processes related to proliferation and differentiation of neuronal progenitor cells during early development which led the focus of the research on neuronal degenerative diseases like Alzheimer’s and Down syndrome. However, DYRK1A is overexpressed in a variety of cancer cells and suspected to be the cause for the higher cancer susceptibility of children with Down syndrome to develop acute megakaryoplastic leukemia (AMKL) or acute lymphoblastic leukemia (ALL) and DYRK1A is found at elevated concentrations in brain tumors.

A second family member DYRK1B mediates survival and differentiation and can be found in an up to 10fold elevated level in solid tumors. DYRKIB blocks the cell cycling in the G0 phase and increases the expression of antioxidant genes that decrease reactive oxygen species (ROS) levels. Both mechanism lead to an increase the cell viability of quiescent cells. Quiescent cells are a major problem in the treatment of cancer. They are relatively insensitive to most chemotherapies or radiation therapies that mainly target dividing cells and can therefor escape these kind of treatments, causing a risk that these cells reenter the cell cycle, regrow and in consequence lead to a recurrence of the tumor.

Publications on DYRK1A

2018

• Czarna A, Wang J, Zelencova D, Liu Y, Deng X, Choi HG, Zhang T, Zhou W, Chang JW, Kildalsen H, Seternes OM, Gray NS, Engh RA, Rothweiler U. Novel scaffolds for Dual specificity tyrosine-phosphorylation-regulated kinase (DYRK1A) inhibitors.J Med Chem. 2018 Sep 3;61(17):7560-7572. doi: 10.1021/acs.jmedchem.7b01847. Epub 2018 Aug 23.PMID:30095246

2016

• Rothweiler, Ulli; Stensen, Wenche; Brandsdal, Bjørn Olav; Isaksson, Johan; Leeson, Frederick Alan; Engh, Richard Alan; Svendsen, John Sigurd Mjøen. Probing the ATP-Binding Pocket of Protein Kinase DYRK1A with Benzothiazole Fragment Molecules. Journal of Medicinal Chemistry 2016; Volum 59 (21). ISSN 0022-2623.s 9814 - 9824.s doi: 10.1021/acs.jmedchem.6b01086.

2015

• Rothweiler, Ulli; Eriksson, Jonas; Stensen, Wenche; Leeson, Frederick Alan; Engh, Richard Alan; Svendsen, John Sigurd. Luciferin and derivatives as a DYRK selective scaffold for the design of protein kinase inhibitors. European Journal of Medicinal Chemistry 2015; Volum 94. ISSN 0223-5234.s 140 - 148.s doi: 10.1016/j.ejmech.2015.02.035.

• Alexeeva, Marina; Åberg, Espen; Engh, Richard Alan; Rothweiler, Ulli. The structure of a dual-specificity tyrosine phosphorylation-regulated kinase 1A-PKC412 complex reveals disulfide-bridge formation with the anomalous catalytic loop HRD(HCD) cysteine. Acta Crystallographica Section D: Biological Crystallography 2015; Volum 71. ISSN 0907-4449.s 1207 - 1215.s doi: 10.1107/S1399004715005106.