7QUE

The STK17A (DRAK1) Kinase Domain Bound to CKJB68

7QUE の概要

• エントリーDOI: 10.2210/pdb7que/pdb
• 分子名称: Serine/threonine-protein kinase 17A, ~{N}-(phenylmethyl)-7,10-dioxa-13,17,18,21-tetrazatetracyclo[12.5.2.1^{2,6}.0^{17,20}]docosa-1(20),2(22),3,5,14(21),15,18-heptaene-5-carboxamide (3 entities in total)
• 機能のキーワード: kinase small-molecule binder inhibitor macrocycle, transferase
• 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: 63867.32

構造登録者

Mathea, S.,Preuss, F.,Chatterjee, D.,Dederer, V.,Kurz, C.G.,Amrhein, J.A.,Hanke, T.,Knapp, S. (登録日: 2022-01-17, 公開日: 2022-02-02, 最終更新日: 2024-01-31)

主引用文献

Kurz, C.G.,Preuss, F.,Tjaden, A.,Cusack, M.,Amrhein, J.A.,Chatterjee, D.,Mathea, S.,Berger, L.M.,Berger, B.T.,Kramer, A.,Weller, M.,Weiss, T.,Muller, S.,Knapp, S.,Hanke, T.
Illuminating the Dark: Highly Selective Inhibition of Serine/Threonine Kinase 17A with Pyrazolo[1,5- a ]pyrimidine-Based Macrocycles.
J.Med.Chem., 65:7799-7817, 2022

PubMed Abstract: Serine/threonine kinase 17A (death-associated protein kinase-related apoptosis-inducing protein kinase 1─DRAK1) is a part of the death-associated protein kinase (DAPK) family and belongs to the so-called dark kinome. Thus, the current state of knowledge of the cellular function of DRAK1 and its involvement in pathophysiological processes is very limited. Recently, DRAK1 has been implicated in tumorigenesis of glioblastoma multiforme (GBM) and other cancers, but no selective inhibitors of DRAK1 are available yet. To this end, we optimized a pyrazolo[1,5-]pyrimidine-based macrocyclic scaffold. Structure-guided optimization of this macrocyclic scaffold led to the development of CK156 (), which displayed high in vitro potency ( = 21 nM) and selectivity in kinomewide screens. Crystal structures demonstrated that CK156 () acts as a type I inhibitor. However, contrary to studies using genetic knockdown of DRAK1, we have seen the inhibition of cell growth of glioma cells in 2D and 3D culture only at low micromolar concentrations.

PubMed: 35608370
DOI: 10.1021/acs.jmedchem.2c00173

実験手法

X-RAY DIFFRACTION (2.4 Å)