Azole-based inhibitors of AKT/PKB for the treatment of cancer

• Published in: Bioorganic & medicinal chemistry letters 2010-03, Vol.20 (5), p.1559-1564
• Main Authors: Zeng, Qingping, Allen, John G., Bourbeau, Matthew P., Wang, Xianghong, Yao, Guomin, Tadesse, Seifu, Rider, James T., Yuan, Chester C., Hong, Fang-Tsao, Lee, Matthew R., Zhang, Shiwen, Lofgren, Julie A., Freeman, Daniel J., Yang, Suijin, Li, Chun, Tominey, Elizabeth, Huang, Xin, Hoffman, Douglas, Yamane, Harvey K., Fotsch, Christopher, Dominguez, Celia, Hungate, Randall, Zhang, Xiaoling
• Format: Article
• Language: English
• Subjects: AKT; Animals; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Azoles - chemistry; Azoles - pharmacokinetics; Azoles - therapeutic use; Binding Sites; Biological and medical sciences; Cancer; Crystallography, X-Ray; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; Cyclic AMP-Dependent Protein Kinases - metabolism; Cyclin-Dependent Kinase 2 - antagonists & inhibitors; Cyclin-Dependent Kinase 2 - metabolism; Drug Design; General aspects; Medical sciences; Mice; Mice, Nude; Neoplasms - drug therapy; Pharmacology. Drug treatments; PKB; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Sprague-Dawley; SAR studies; Structure-Activity Relationship; Xenograft Model Antitumor Assays
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.01.067

Through a combination of screening and structure-based rational design, we have discovered a series of N 1-(5-(heterocyclyl)-thiazol-2-yl)-3-(4-trifluoromethylphenyl)-1,2-propanediamines that were developed into potent ATP competitive inhibitors of AKT. Studies of linker strand-binding adenine isosteres identified SAR trends in potency and selectivity that were consistent with binding interactions observed in structures of the inhibitors bound to AKT1 and to the counter-screening target PKA. One compound was shown to have acceptable pharmacokinetic properties and to be a potent inhibitor of AKT signaling and of in vivo xenograft tumor growth in a preclinical model of glioblastoma.