PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways inhibitors as anticancer agents: Structural and pharmacological perspectives

The protein kinases regulate cellular functions such as transcription, translation, proliferation, growth and survival by the process of phosphorylation. Over activation of signaling pathways play a major role in oncogenesis. The PI3K signaling pathway is dysregulated almost in all cancers due to the amplification, genetic mutation of PI3K gene and the components of the PI3K pathway themselves. Stimulation of the PI3K/Akt/mTOR and Ras/Raf/MEK/ERK pathways enhances growth, survival, and metabolism of cancer cells. Recently, the PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways have been identified as promising therapeutic targets for cancer therapy. The kinase inhibitors with enhanced specificity and improved pharmacokinetics have been considered for design and development of anticancer agents. This review focuses primarily on the Ras/Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways as therapeutic targets of anticancer drugs, their specific and dual inhibitors, structure activity relationships (SARs) and inhibitors under clinical trials. (C) 2016 Elsevier Masson SAS. All rights reserved.