Compounds that inhibit the kinase activity of phospoinostidie 3-kinase (PI3Kα) for the treatment of cancer.
- Potential therapeutic targeted to pathway without a clinically approved inhibitor.
- Provides a useful pharmacological probe for research purposes.
Cancer kills almost 600,000 Americans each year and is the second leading cause of death in the United States. In order to grow, cancer cells must have the ability to sustain angiogenesis, the growth of new blood vessels. Without access to blood vessels, tumors do not receive the nutrients and oxygen that are critical for the survival and proliferation of cancer cells. One key cellular pathway that regulates angiogenesis is the PI3K/Akt pathway. Mutations in PI3K (phospoinostidie 3-kinase) can lead to increased vascular endothelial growth factor (VEGF), which can then bind to VEGF receptors on blood vessel endothelial cells and attract blood vessels to the tumor site. Inhibitors of PI3K may have anti-tumor effects. Compounds as kinase inhibitors are currently in development, but there is currently only one clinically approved PI3K inhibitor (idelalisib).
Of the PI3K family of enzymes, class 1A (PI3Kα) is the most well-characterized, as it is overexpressed in many human cancers including ovarian, breast, gastric, and hepatic cancer. Emory University researchers have designed and synthesized a series of PI3Kα inhibitors. The researchers have identified imidazo[1,2-a]pyridine derivatives which show potent (low nM) activity in enzymatic and cellular proliferation assays. Inhibitors of this lipid kinase may have potent anti-tumor effects and lead to new cancer therapeutics.
Compounds have been generated and tested against isoforms of PI3K, including alpha, beta, gamma and delta.