Current developments in PI3K-based anticancer agents: Designing strategies, biological activity, selectivity, structure-activity correlation, and docking insight.

The phospatidylinositol-3 kinase (PI3K) pathway is a critical intracellular signalling mechanism that is changed or amplified in a variety of cancers, including breast, gastric, ovarian, colorectal, prostate, glioma, and endometrial. PI3K signalling is important for cancer cell survival, angiogenesis, and metastasis, making it a promising therapeutic target. The PI3K kinases in their different isoforms, namely α, β, δ, and γ, encode PIK3CA, PIK3CB, PIK3CD, and PIK3CG genes. Specific gene mutation or overexpression of the protein is responsible for the therapeutic failure of current therapeutics. There are several current and completed clinical trials using PI3K inhibitors (pan, isoform-specific, and dual PI3K/mTOR) to develop effective PI3K inhibitors capable of overcoming resistance to existing drugs. However, the bulk of these inhibitors have had their indications revoked or voluntarily withdrawn due to concerns about their harmful consequences. Several inhibitors containing medicinally privileged scaffolds like thiazole, triazine, benzimidazole, podophyllotoxin, pyridine, quinazoline, thieno-triazole, pyrimidine, triazole, benzofuran, imidazo-pyridazine, oxazole, coumarin, and azepine derivatives have been explored to target the PI3K pathway and/or a specific isoform in the current overview. This article reviews the structure, biological activities, and clinical status of PI3K inhibitors. It focuses on the development techniques, docking insight, and structure-activity connections of PI3K-based inhibitors. The findings provide useful insights and future approaches for the development of promising PI3K-based inhibitors.