7QUE

The STK17A (DRAK1) Kinase Domain Bound to CKJB68

Summary for 7QUE

• Entry DOI: 10.2210/pdb7que/pdb
• Descriptor: 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)
• Functional Keywords: kinase small-molecule binder inhibitor macrocycle, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 63867.32

Authors

Mathea, S.,Preuss, F.,Chatterjee, D.,Dederer, V.,Kurz, C.G.,Amrhein, J.A.,Hanke, T.,Knapp, S. (deposition date: 2022-01-17, release date: 2022-02-02, Last modification date: 2024-01-31)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.4 Å)