Phosphatidylinositol 3 kinase (PI3K) inhibitors as new weapon to combat cancer

Eur J Med Chem. 2019 Dec 1:183:111718. doi: 10.1016/j.ejmech.2019.111718. Epub 2019 Sep 20.

Abstract

Phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequently activated pathogenic signaling cascades in human malignancies. PI3K is genetically mutated or overexpressed in a wide variety of cancers including ovarian, breast, prostate, gastric, colorectal, glioblastoma, endometrial and brain cancers. Studies are still ongoing to find more efficient and selective PI3K inhibitors or dual PI3K inhibitors to overcome the resistance to the current inhibitors. This review will focus on the three main classes of PI3K inhibitors with efficacious antitumor activity which are: isoform-selective PI3K inhibitors, dual pan-Class I PI3K/m-TOR inhibitors, and pan-Class I PI3K inhibitors without significant m-TOR activity. Isoform-selective PI3K inhibitors are classified into four classes IA, IB, II, and III. Moreover, SAR among each class, together with the biological activity will be discussed. In addition, the new scopes for the design of novel candidates to overcome emerging resistance will be highlighted as well.

Keywords: AKT; Cancer; PI3K; PI3K inhibitors; m-TOR.

Publication types

  • Review

MeSH terms

  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Antineoplastic Agents* / therapeutic use
  • Drug Design
  • Drug Resistance, Multiple
  • Humans
  • Molecular Targeted Therapy
  • Mutation
  • Neoplasms / drug therapy
  • Neoplasms / enzymology
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Protein Kinase Inhibitors* / therapeutic use

Substances

  • Antineoplastic Agents
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors