Fragment based discovery of a novel and selective PI3 kinase inhibitor

• Published in: Bioorganic & medicinal chemistry letters 2011-11, Vol.21 (21), p.6586-6590
• Main Authors: Hughes, Samantha J., Millan, David S., Kilty, Iain C., Lewthwaite, Russell A., Mathias, John P., O’Reilly, Mark A., Pannifer, Andrew, Phelan, Anne, Stühmeier, Frank, Baldock, Darren A., Brown, David G.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cell Membrane Permeability - drug effects; Drug Discovery; Drug Stability; drugs; enzyme inhibitors; Fragment; Kinase; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; screening; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.07.117

We report the use of fragment screening and fragment based drug design to develop a PI3γ kinase fragment hit into a lead. Initial fragment hits were discovered by high concentration biochemical screening, followed by a round of virtual screening to identify additional ligand efficient fragments. These were developed into potent and ligand efficient lead compounds using structure guided fragment growing and merging strategies. This led to a potent, selective, and cell permeable PI3γ kinase inhibitor with good metabolic stability that was useful as a preclinical tool compound.