7AKE

Structure of DYRK1A in complex with compound 58

7AKE の概要

• エントリーDOI: 10.2210/pdb7ake/pdb
• 関連するPDBエントリー: 7aj2 7aj4 7aj5 7aj7 7aj8 7aja 7ajm 7ajs 7ajv 7ajw 7ajy 7ak2 7aka 7akb
• 分子名称: Dual specificity tyrosine-phosphorylation-regulated kinase 1A, 4-[3-[(2~{S})-2-(6-bromanylpyridin-2-yl)oxypropyl]-2-methyl-imidazo[4,5-b]pyridin-5-yl]pyridine-2,6-diamine, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: serine/threonine-protein kinase, phosphoprotein, kinase selectivity, transferase, sbdd, small molecule inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 84238.36

構造登録者

Dokurno, P.,Surgenor, A.E.,Kotschy, A. (登録日: 2020-09-30, 公開日: 2021-05-26, 最終更新日: 2024-11-13)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.3 Å)