Phosphoinositide 3-kinase gamma (PI3Kgamma) inhibitors for the treatment of inflammation and autoimmune disease.
Phosphoinositide 3-kinase gamma (PI3Kgamma) is a lipid kinase in leukocytes that generates phosphatidylinositol 3,4,5-trisphosphate to recruit and activate downstream signaling molecules. Distinct from other members in the PI3K family, PI3Kgamma is activated by G-protein coupled-receptors responding to chemotactic ligands. PI3Kgamma plays an important role in migration of both myeloid and lymphoid cells. It is also required for other leukocyte functions such as neutrophil oxidative burst, T cell proliferation and mast degranulation. Mice with PI3Kgamma inactivated by genetic or pharmacological approaches are protected from disease development in a number of inflammation and autoimmune disease models. The function of PI3Kgamma depends on its kinase activity and therefore it has been suggested by many reports that small molecules inhibiting its kinase activity could be promising for the treatment of inflammation and autoimmune diseases. Over the last five years, a number of pharmaceutical companies have reported a wide variety of PI3Kgamma inhibitors, of which several x-ray crystal structures with PI3Kgamma have been elucidated. The structural characteristics and selectivity profiles of these inhibitors, in particular thiazolidinones and 2-aminoheterocycles, and those disclosed in related patent applications are summarized in this review.
Venable
Jennifer D
JD
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA92121, USA. wleung@its.jnj.com
Ameriks
Michael K
MK
Blevitt
Jonathan M
JM
Thurmond
Robin L
RL
Fung-Leung
Wai-Ping
WP
D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy*; D058544:Class Ib Phosphatidylinositol 3-Kinase; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D010330:Patents as Topic; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D045162:Thiazolidinediones / Q000737:chemistry / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D045162:Thiazolidinediones; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human; C546764:Pik3cg protein, mouse