Design, synthesis, and structure-activity relationships of 3-ethynyl-1H-indazoles as inhibitors of the phosphatidylinositol 3-kinase signaling pathway.
A new series of 3-ethynyl-1H-indazoles has been synthesized and evaluated in both biochemical and cell-based assays as potential kinase inhibitors. Interestingly, a selected group of compounds identified from this series exhibited low micromolar inhibition against critical components of the PI3K pathway, targeting PI3K, PDK1, and mTOR kinases. A combination of computational modeling and structure-activity relationship studies reveals a possible novel mode for PI3K inhibition, resulting in a PI3Kα isoform-specific compound. Hence, by targeting the most oncogenic mutant isoform of PI3K, the compound displays antiproliferative activity both in monolayer human cancer cell cultures and in three-dimensional tumor models. Because of its favorable physicochemical, in vitro ADME and drug-like properties, we propose that this novel ATP mimetic scaffold could prove useful in deriving novel selecting and multikinase inhibitors for clinical use.
Sanford-Burnham Medical Research Institute, La Jolla, California 92037, United States.
Elisa
E
Barile
Surya K
SK
De
Coby B
CB
Carlson
Vida
V
Chen
Christine
C
Knutzen
Megan
M
Riel-Mehan
Li
L
Yang
Russell
R
Dahl
Gary
G
Chiang
Maurizio
M
Pellecchia
D045744:Cell Line, Tumor; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D062105:Molecular Docking Simulation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007191:Indazoles; D019869:Phosphatidylinositol 3-Kinases