Targeting Phosphoinositide 3-kinase: Moving Towards Therapy

Biochim Biophys Acta. 2008 Jan;1784(1):159-85. doi: 10.1016/j.bbapap.2007.10.003. Epub 2007 Oct 12.

Abstract

Phosphoinositide 3-kinases (PI3K) orchestrate cell responses including mitogenic signaling, cell survival and growth, metabolic control, vesicular trafficking, degranulation, cytoskeletal rearrangement and migration. Deregulation of the PI3K pathway occurs by activating mutations in growth factor receptors or the PIK3CA locus coding for PI3Kalpha, by loss of function of the lipid phosphatase and tensin homolog deleted in chromosome ten (PTEN/MMAC/TEP1), by the up-regulation of protein kinase B (PKB/Akt), or the impairment of the tuberous sclerosis complex (TSC1/2). All these events are linked to growth and proliferation, and have thus prompted a significant interest in the pharmaceutical targeting of the PI3K pathway in cancer. Genetic targeting of PI3Kgamma (p110gamma) and PI3Kdelta (p110delta) in mice has underlined a central role of these PI3K isoforms in inflammation and allergy, as they modulate chemotaxis of leukocytes and degranulation in mast cells. Proof-of-concept molecules selective for PI3Kgamma have already successfully alleviated disease progress in murine models of rheumatoid arthritis and lupus erythematosus. As targeting PI3K moves forward to therapy of chronic, non-fatal disease, safety concerns for PI3K inhibitors increase. Many of the present inhibitor series interfere with target of rapamycin (TOR), DNA-dependent protein kinase (DNA-PK(cs)) and activity of the ataxia telangiectasia mutated gene product (ATM). Here we review the current disease-relevant knowledge for isoform-specific PI3K function in the above mentioned diseases, and review the progress of >400 recent patents covering pharmaceutical targeting of PI3K. Currently, several drugs targeting the PI3K pathway have entered clinical trials (phase I) for solid tumors and suppression of tissue damage after myocardial infarction (phases I,II).

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cardiovascular Diseases / drug therapy
  • Cardiovascular Diseases / enzymology
  • Cardiovascular Diseases / metabolism
  • Cell Cycle / drug effects
  • Cell Proliferation / drug effects
  • Enzyme Activation
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Immune System Diseases / drug therapy
  • Immune System Diseases / enzymology
  • Immune System Diseases / metabolism
  • Metabolic Diseases / drug therapy
  • Metabolic Diseases / enzymology
  • Metabolic Diseases / metabolism
  • Neoplasms / drug therapy
  • Neoplasms / enzymology
  • Neoplasms / metabolism
  • PTEN Phosphohydrolase / metabolism*
  • Phosphatidylinositol 3-Kinases / chemistry
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / drug effects
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins / metabolism

Substances

  • Enzyme Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • TSC1 protein, human
  • Tsc1 protein, mouse
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human