The first Oup includes inhibitors of the isoforms of PI3K class IA. These enzymes are heterodimers of a catalytic lipid kinase p110 subunit and a regulatory subunit, the receptor binding site or the adapter, activation and localization of PI3K mediated dimer composed. There are three genes, PIK3CA AMG-208 and PIK3CB PIK3CD that encode the highly homologous p110 catalytic isoforms, P110, P110, P110 and ? respectively. ? p110 expression is largely immune cells and h Hematopoietic RESTRICTION about.Limited P110 p110 then expressed ethical and fa Ubiquitous one. p110 is for signaling and tumor growth by mutations and / or PIK3CA oncogenic tyrosine kinases or ras mutant, driven essentially w while p110 responds to G-protein coupled receptors and is the major isoform mediating tumorigenesis in PTEN-deficient cells.
A number of specific or pan-PI3K isoform-specific antagonist in Phase I clinical development and. To go Ren NVP BEZ235, NVP BGT226, GDC 0941, XL 765, XL 147, SF1126, CAL 101 and GSK1059615. These are compounds that bind ATPmimetics competitively and reversibly in the ATP-binding pocket of the kinase Dom ne of p110. Except CAL 101, which are specific kinase p110 ? other small molecules active against all P110 isoforms, including normal oncogenic mutants of p110. Some of them also have inhibitory activity T related to phosphatidylinositol-3-kinase kinases such as mTOR serine / threonine kinase. After P110 antagonist inhibitors of Akt isoforms. These compounds showed antitumor activity T against human xenografts and were recently studied.
A 443654 and GSK690693 are ATP-competitive kinase inhibitors act pan They showed antitumor activity t in pr Clinical models and have recently entered Phase I studies. Allosteric inhibitors of the interaction with its PH-Akt Cathedral ne And / or hinge region f Thus promotes an inactive conformation of the enzyme, are also in development. MK 2206 is a highly selective ATP uncompetitive allosteric inhibitor or Akt1, Akt2 and Akt3. This compound effectively inhibits Akt and its downstream Rtigen effectors in vivo and causes marked suppression of the growth of breast cancer xenografts with mutations of the PI3K and HER2 gene amplification. Early phase I clinical data of patients with advanced solid tumors showed inhibition of Akt in mononuclear P Ren cells of peripheral blood and a good reps Possibility.
By the high Sequenzidentit t among Kinasedom Ne AKT1, AKT2 and Akt3 is expected that the development of isoform-selective modulators is powerful to be difficult. A third group of the compounds for more interrupt PI3K inhibitors are designed mTOR serine / threonine kinase. This kinase regulates protein translation and functions in both multi-protein complexes, the shares mTOR itself: TORC1 and TORC2 with RAPTOR YEARS connected ring Rictor. Rapamycin and its analogs preferentially target TORC1. mTOR is an important component of the PI3K oncogenesis is entered born at different levels.