Abstract
6-phenylpurines were identified as novel, ATP-competitive inhibitors of protein kinase B (PKB/Akt) from a fragment-based screen and were rapidly progressed to potent compounds using iterative protein-ligand crystallography with a PKA-PKB chimeric protein. An elaborated lead compound showed cell growth inhibition and effects on cellular signaling pathways characteristic of PKB inhibition.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adenosine Triphosphate / metabolism
-
Antineoplastic Agents / chemical synthesis*
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / pharmacology
-
Cell Line, Tumor
-
Cell Proliferation / drug effects
-
Crystallography, X-Ray
-
Cyclic AMP-Dependent Protein Kinases / genetics
-
Drug Design
-
Drug Screening Assays, Antitumor
-
Humans
-
Ligands
-
Models, Molecular*
-
Protein Binding
-
Protein Structure, Tertiary
-
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
-
Proto-Oncogene Proteins c-akt / chemistry*
-
Proto-Oncogene Proteins c-akt / genetics
-
Purines / chemical synthesis*
-
Purines / chemistry
-
Purines / pharmacology
-
Recombinant Fusion Proteins / chemistry
-
Recombinant Fusion Proteins / genetics
-
Structure-Activity Relationship
Substances
-
Antineoplastic Agents
-
Ligands
-
Purines
-
Recombinant Fusion Proteins
-
Adenosine Triphosphate
-
Proto-Oncogene Proteins c-akt
-
Cyclic AMP-Dependent Protein Kinases