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Details on Person A variety of inhibitors capable of blocking the phosphoinosi...
| Class:Id | Summation:9732467 |
|---|---|
| _displayName | A variety of inhibitors capable of blocking the phosphoinosi... |
| _timestamp | 2021-05-27 12:54:17 |
| created | [InstanceEdit:9732444] Stephan, Ralf, 2021-05-27 |
| literatureReference | [LiteratureReference:2399890] NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations [LiteratureReference:2399826] Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity [LiteratureReference:2399821] Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor [LiteratureReference:2399837] Novel phosphoinositide 3-kinase/mTOR dual inhibitor, NVP-BGT226, displays potent growth-inhibitory activity against human head and neck cancer cells in vitro and in vivo [LiteratureReference:2399754] Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide [LiteratureReference:2399733] Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors [LiteratureReference:2399831] The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer [LiteratureReference:1358728] Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941 [LiteratureReference:2399785] Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction [LiteratureReference:2399870] Targeting the phosphoinositide 3-kinase pathway in cancer [LiteratureReference:2459950] A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling [LiteratureReference:2459949] A drug targeting only p110? can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types [LiteratureReference:2399685] Cancer-derived mutations in the regulatory subunit p85alpha of phosphoinositide 3-kinase function through the catalytic subunit p110alpha [LiteratureReference:2459963] The p110? and p110? isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis [LiteratureReference:2459988] PI 3-kinase p110beta: a new target for antithrombotic therapy [LiteratureReference:2460012] Functional characterization of an isoform-selective inhibitor of PI3K-p110? as a potential anticancer agent [LiteratureReference:2460069] Phosphatidylinositol 3-kinase-? inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals |
| text | A variety of inhibitors capable of blocking the phosphoinositide kinase activity of PI3K have been developed. These inhibitors display differential selectivity and inhibit kinase activity of their substrates by distinct mechanisms. For example, the first-generation PI3K inhibitor wortmannin (Wymann et al. 1996) covalently and irreversibly binds all classes of PI3K enzymes, as well as other kinases including mTOR, at a residue critical for catalytic activity. Although wortmannin is precluded from in vivo and clinical use due to its toxicity, it has proven to be a useful tool for in vitro laboratory studies. Newer inhibitors, such as BEZ235, are currently being investigated in Phase I clinical trials. BEZ235 is a dual pan-class I PI3K/mTOR inhibitor that blocks kinase activity by binding competitively to the ATP-binding pocket of these enzymes (Serra et al. 2008, Maira et al. 2008). BGT226 (Chang et al. 2011) and XL765 (Prasad et al. 2011) also inhibits both PI3K class I enzymes and mTOR. Other inhibitors in clinical trials, such as BKM120 (Maira et al. 2012), GDC0941 (Folkes et al. 2008, Junttila et al. 2009) and XL147 (Chakrabarty et al. 2012), are specific for class I PI3Ks and exhibit no activity against mTOR. Current research aims to identify isoform-specific PI3K inhibitors. Small molecule inhibitors that selectively inhibit PIK3CA (p110alpha), e.g. PIK-75 and A66, were used to study the role of p110alpha in signaling and growth of tumor cells (Knight et al. 2006, Sun et al. 2010, Jamieson et al. 2011, Utermark et al. 2012). The PIK3CB (p110beta) specific inhibitor TGX221 has been used in in vitro models of vascular injury (Jackson et al. 2005), and the TGX221 derivative KIN-193 has been shown to block AKT activity and tumor growth in mice with p110beta activation or PTEN loss (Ni et al. 2012). CAL-101 is a PIK3CD (p110delta) specific inhibitor that is being clinically investigated as a therapeutic for lymphoid malignancies (Herman et al. 2010). It is hoped that, in the future, more specific inhibitors, such as those targeting selective PI3K isoforms, will provide optimum treatment while minimizing unwanted side effects. After 2010 several compounds were approved: duvelisib is a specific inhibitor of delta and gamma isoforms of PI3K (Winkler et al, 2013); idelalisib blocks the delta isoform (Lannutti et al, 2011); alpelisib is specific to the alpha isoform (Furet et al, 2013) and copanlisib preferentially blocks the alpha and delta isoforms (Liu et al, 2013). All four drugs are second-line, although copanlisib has fewer gastrointestinal side-effects because it is applied weekly and intravenously (Krause et al, 2018). GDC0941 (pictilisib) was not successful in phase 2 breast cancer trials (Krop et al, 2016). However, it has been shown to prevent SARS-CoV-2 replication in Caco-2 and UKF-RC-2 cells (Klann et al, 2020). |
| (summation) | [Reaction:9732513] PI3K inhibitors bind to Activator:PI3K [Homo sapiens] |
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