7AJM

Structure of DYRK1A in complex with compound 32

Summary for 7AJM

• Entry DOI: 10.2210/pdb7ajm/pdb
• Related: 7aj2 7aj4 7aj5 7aj7 7aj8 7aja
• Descriptor: Dual specificity tyrosine-phosphorylation-regulated kinase 1A, ~{N}-[6-azanyl-4-(1-benzofuran-5-yl)pyridin-2-yl]-2-(methylamino)ethanamide, DIMETHYL SULFOXIDE, ... (4 entities in total)
• Functional Keywords: serine/threonine-protein kinase, phosphoprotein, kinase selectivity, transferase, sbdd, small molecule inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 82899.88

Authors

Dokurno, P.,Surgenor, A.E.,Kotschy, A. (deposition date: 2020-09-29, release date: 2021-05-26, Last modification date: 2024-11-06)

Primary citation

Weber, C.,Sipos, M.,Paczal, A.,Balint, B.,Kun, V.,Foloppe, N.,Dokurno, P.,Massey, A.J.,Walmsley, D.L.,Hubbard, R.E.,Murray, J.,Benwell, K.,Edmonds, T.,Demarles, D.,Bruno, A.,Burbridge, M.,Cruzalegui, F.,Kotschy, A.
Structure-Guided Discovery of Potent and Selective DYRK1A Inhibitors.
J.Med.Chem., 64:6745-6764, 2021

PubMed Abstract: The kinase DYRK1A is an attractive target for drug discovery programs due to its implication in multiple diseases. Through a fragment screen, we identified a simple biaryl compound that is bound to the DYRK1A ATP site with very high efficiency, although with limited selectivity. Structure-guided optimization cycles enabled us to convert this fragment hit into potent and selective DYRK1A inhibitors. Exploiting the structural differences in DYRK1A and its close homologue DYRK2, we were able to fine-tune the selectivity of our inhibitors. Our best compounds potently inhibited DYRK1A in the cell culture and and demonstrated drug-like properties. The inhibition of DYRK1A translated into dose-dependent tumor growth inhibition in a model of ovarian carcinoma.

PubMed: 33975430
DOI: 10.1021/acs.jmedchem.1c00023

Experimental method

X-RAY DIFFRACTION (2.4 Å)