Recent progress towards clinically relevant ATP-competitive Akt inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 27; no. 13; pp. 2838 - 2848
• Main Authors: Huck, Bayard R., Mochalkin, Igor
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.07.2017
• Subjects: Adenosine Triphosphate - chemical synthesis; Adenosine Triphosphate - chemistry; Adenosine Triphosphate - pharmacology; Akt inhibitor; Animals; Clinical candidate; Humans; Kinase inhibitor; Models, Molecular; Molecular Structure; PI3K/Akt/mTOR pathway; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Structure-Activity Relationship; Kinase inhibitor; PI3K/Akt/mTOR pathway; Akt inhibitor; Clinical candidate
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2017.04.090

[Display omitted] The frequency of PI3K/Akt/mTOR (PAM) Pathway mutations in human cancers sparked interest to determine if the pathway is druggable. The modest clinical benefit observed with mTOR rapalogs (temsirolimus and everolimus) provided further motivation to identify additional nodes of pathway inhibition that lead to improved clinical benefit. Akt is a central signaling node of the PAM pathway and could be an ideal target for improved pathway inhibition. Furthermore, inhibitors of Akt may be especially beneficial in tumors with Akt1 mutations. Recently, multiple ATP-competitive Akt inhibitors have been identified and are currently in clinical development. This review details the medicinal chemistry efforts towards identification of these molecules, highlights relevant preclinical data supporting clinical evaluation, and summarizes current clinical development plans.