Discovery and optimization of potent and selective imidazopyridine and imidazopyridazine mTOR inhibitors

mTOR is a critical regulator of cellular signaling downstream of multiple growth factors. The mTOR/PI3K/AKT pathway is frequently mutated in human cancers and is thus an important oncology target. Herein we report the evolution of our program to discover ATP-competitive mTOR inhibitors that demonstr...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2012-08, Vol.22 (15), p.4967-4974
Hauptverfasser:	Peterson, Emily A., Boezio, Alessandro A., Andrews, Paul S., Boezio, Christiane M., Bush, Tammy L., Cheng, Alan C., Choquette, Deborah, Coats, James R., Colletti, Adria E., Copeland, Katrina W., DuPont, Michelle, Graceffa, Russell, Grubinska, Barbara, Kim, Joseph L., Lewis, Richard T., Liu, Jingzhou, Mullady, Erin L., Potashman, Michele H., Romero, Karina, Shaffer, Paul L., Stanton, Mary K., Stellwagen, John C., Teffera, Yohannes, Yi, Shuyan, Cai, Ti, La, Daniel S.
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Benzimidazoles - chemistry Binding Sites Binding, Competitive Biological and medical sciences Crystallography, X-Ray Drug Design Drug Evaluation, Preclinical Half-Life Humans Imidazoles - chemistry Imidazopyridazine Imidazopyridine Kinase inhibitor Male Medical sciences Mice Microsomes, Liver - metabolism mTOR Oncology Pharmacology. Drug treatments Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - metabolism Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacokinetics Protein Structure, Tertiary Pyridazines - chemical synthesis Pyridazines - chemistry Pyridazines - pharmacokinetics Pyridines - chemical synthesis Pyridines - chemistry Pyridines - pharmacokinetics Rats, Sprague-Dawley Signal Transduction - drug effects Structure-Activity Relationship TOR Serine-Threonine Kinases - antagonists & inhibitors TOR Serine-Threonine Kinases - metabolism
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Zusammenfassung:	mTOR is a critical regulator of cellular signaling downstream of multiple growth factors. The mTOR/PI3K/AKT pathway is frequently mutated in human cancers and is thus an important oncology target. Herein we report the evolution of our program to discover ATP-competitive mTOR inhibitors that demonstrate improved pharmacokinetic properties and selectivity compared to our previous leads. Through targeted SAR and structure-guided design, new imidazopyridine and imidazopyridazine scaffolds were identified that demonstrated superior inhibition of mTOR in cellular assays, selectivity over the closely related PIKK family and improved in vivo clearance over our previously reported benzimidazole series.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2012.06.033