Phosphatidylinositol 3-Kinase (PI3K) and phosphatidylinositol 3-kinase-related kinase (PIKK) inhibitors: importance of the morpholine ring.
Phosphatidylinositol 3-kinases (PI3Ks) and phosphatidylinositol 3-kinase-related protein kinases (PIKKs) are two related families of kinases that play key roles in regulation of cell proliferation, metabolism, migration, survival, and responses to diverse stresses including DNA damage. To design novel efficient strategies for treatment of cancer and other diseases, these kinases have been extensively studied. Despite their different nature, these two kinase families have related origin and share very similar kinase domains. Therefore, chemical inhibitors of these kinases usually carry analogous structural motifs. The most common feature of these inhibitors is a critical hydrogen bond to morpholine oxygen, initially present in the early nonspecific PI3K and PIKK inhibitor 3 (LY294002), which served as a valuable chemical tool for development of many additional PI3K and PIKK inhibitors. While several PI3K pathway inhibitors have recently shown promising clinical responses, inhibitors of the DNA damage-related PIKKs remain thus far largely in preclinical development.
Biomedical Research Center, University Hospital Hradec Kralove , Sokolska 81, 500 05 Hradec Kralove, Czech Republic.
Martin
M
Andrs
Jan
J
Korabecny
Daniel
D
Jun
Zdenek
Z
Hodny
Jiri
J
Bartek
Kamil
K
Kuca
D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry*; D058539:Phosphatidylinositol 3-Kinase / Q000737:chemistry* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects
D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C037574:morpholine; D058539:Phosphatidylinositol 3-Kinase; D017346:Protein Serine-Threonine Kinases