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Biochemical Discovery, Intracellular Evaluation, and Crystallographic Characterization of Synthetic and Natural Product Adenosine 3',5'-Cyclic Monophosphate-Dependent Protein Kinase A (PKA) Inhibitors.

Brice A P WilsonNing LiJuliana A Martinez FiescoMasoumeh DalilianDongdong WangEmily A SmithAntony WamiruRohan ShahEkaterina I GoncharovaJohn A A BeutlerTanja GrkovicPing ZhangBarry R Oâ Keefe
Published in: ACS pharmacology & translational science (2023)
The recent demonstration that adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase A (PKA) plays an oncogenic role in a number of important cancers has led to a renaissance in drug development interest targeting this kinase. We therefore have established a suite of biochemical, cell-based, and structural biology assays for identifying and evaluating new pharmacophores for PKA inhibition. This discovery process started with a 384-well high-throughput screen of more than 200,000 substances, including fractionated natural product extracts. Identified active compounds were further prioritized in biochemical, biophysical, and cell-based assays. Priority lead compounds were assessed in detail to fully characterize several previously unrecognized PKA pharmacophores including the generation of new X-ray crystallography structures demonstrating unique interactions between PKA and bound inhibitor molecules.
Keyphrases
  • protein kinase
  • high throughput
  • single cell
  • cell therapy
  • high resolution
  • small molecule
  • cancer therapy
  • stem cells
  • computed tomography
  • bone marrow
  • magnetic resonance
  • drug delivery