2. Academic Validation
  3. Illuminating the Dark: Highly Selective Inhibition of Serine/Threonine Kinase 17A with Pyrazolo[1,5- a]pyrimidine-Based Macrocycles

Illuminating the Dark: Highly Selective Inhibition of Serine/Threonine Kinase 17A with Pyrazolo[1,5- a]pyrimidine-Based Macrocycles

  • J Med Chem. 2022 Jun 9;65(11):7799-7817. doi: 10.1021/acs.jmedchem.2c00173.
Christian G Kurz 1 2,  Franziska Preuss 1 2,  Amelie Tjaden 1 2,  Martin Cusack 3,  Jennifer Alisa Amrhein 1 2,  Deep Chatterjee 1 2,  Sebastian Mathea 1 2,  Lena Marie Berger 1 2,  Benedict-Tilman Berger 1 2,  Andreas Krämer 1 2 4,  Michael Weller 3,  Tobias Weiss 3,  Susanne Müller 1 2,  Stefan Knapp 1 2,  Thomas Hanke 1 2
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Straße 9, Frankfurt 60438, Germany.
  • 2 Structural Genomics Consortium, Buchman Institute for Molecular Life Science (BMLS), Max-von-Laue-Straße 15, Frankfurt 60438, Germany.
  • 3 Department of Neurology and Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, Frauenklinikstrasse 26, Zurich 8091, Switzerland.
  • 4 Frankfurt Cancer Institute (FCI), Paul-Ehrlich-Straße 42-44, Frankfurt 60596, Germany.
PMID: 35608370 DOI: 10.1021/acs.jmedchem.2c00173
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-a]pyrimidine-based macrocyclic scaffold. Structure-guided optimization of this macrocyclic scaffold led to the development of CK156 (34), which displayed high in vitro potency (KD = 21 nM) and selectivity in kinomewide screens. Crystal structures demonstrated that CK156 (34) 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.

Figures
Products