Natural products as a source of chemical diversity in cyclic-AMP-dependent Protein Kinase A (PKA) inhibitor discovery

Authors

• K Amini
• F Pala
• M Bosticardo
• S Dinges
• L Notarangelo

Abstract

cAMP dependent protein kinase A (PKA) enzymatic activity is a central cellular signaling node underlying many fundamental physiological processes. PKA dysregulation is associated with a number of human diseases including Cushing’s syndrome, Carney Complex disorders, and certain cancers. This cohort of PKA dependent diseases includes fibrolamellar hepatocellular carcinoma (FLHCC), a rare largely incurable liver cancer uniquely driven by the overexpression of an oncogenic fusion between an HSP40 family member, DNAJB1, and the catalytic domain of PKA alpha, PRKACA. This fusion protein (J-PKAcα) is enzymatically active and drives FLHCC tumor growth, making it an attractive target for inhibitor discovery. We implemented a high throughput screening campaign of >140,000 fractionated natural products extracts to discover pharmacophores evaluated for J-PKAcα inhibition, fusion specificity, direct binding, intracellular activity, and x-ray crystallography. This screen revealed several previously unreported PKA inhibitors which may form the foundation of future medicinal chemistry efforts to optimize these scaffolds for translational applications.

Scientific Focus Area: Molecular Pharmacology

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