BioPAX pathway converted from "PI3K inhibitors block PI3K catalytic activity" in the Reactome database. PI3K inhibitors block PI3K catalytic activity PI3K inhibitors block PI3K catalytic activity 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. For a recent review, please refer to Liu et al. 2009. Authored: Orlic-Milacic, M, 2012-07-18 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 Converted from EntitySet in Reactome Reactome DB_ID: 2399811 1 cytosol GO 0005829 PI3K/mutant PI3K inhibitors [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity BKM120 [cytosol] GDC0941 [cytosol] XL147 [cytosol] PX-866 [cytosol] LY294002 [cytosol] wortmannin [cytosol] BGT226 [cytosol] BEZ235 [cytosol] XL765 [cytosol] Reactome Guide to Pharmacology 7878 Guide to Pharmacology 5682 Guide to Pharmacology 7963 Guide to Pharmacology 7941 Guide to Pharmacology 6004 Guide to Pharmacology 6060 Guide to Pharmacology 7951 Guide to Pharmacology 7950 Guide to Pharmacology 7964 Converted from EntitySet in Reactome Reactome DB_ID: 2400011 1 plasma membrane GO 0005886 PI3K mutants,Activator:PI3K [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 2400008 1 PI3K Inhibitors:PI3K [cytosol] PI3K Inhibitors:PI3K Converted from EntitySet in Reactome Reactome DB_ID: 2399811 1 Converted from EntitySet in Reactome Reactome DB_ID: 2400011 1 Homo sapiens NCBI Taxonomy 9606 Reactome Database ID Release 82 2400008 Database identifier. Use this URL to connect to the web page of this instance in Reactome: Reactome R-HSA-2400008 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: Reactome Database ID Release 82 2400009 Database identifier. Use this URL to connect to the web page of this instance in Reactome: Reactome R-HSA-2400009 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: 18754654 Pubmed 2008 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 Folkes, Adrian J Ahmadi, Khatereh Alderton, Wendy K Alix, Sonia Baker, Stewart J Box, Gary Chuckowree, Irina S Clarke, Paul A Depledge, Paul Eccles, Suzanne A Friedman, Lori S Hayes, Angela Hancox, Timothy C Kugendradas, Arumugam Lensun, Letitia Moore, Pauline Olivero, Alan G Pang, Jodie Patel, Sonal Pergl-Wilson, Giles H Raynaud, Florence I Robson, Anthony Saghir, Nahid Salphati, Laurent Sohal, Sukhjit Ultsch, Mark H Valenti, Melanie Wallweber, Heidi J A Wan, Nan Chi Wiesmann, C Workman, Paul Zhyvoloup, A Zvelebil, Marketa J Shuttleworth, Stephen J J. Med. Chem. 51:5522-32 21976531 Pubmed 2011 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 Chang, Kwang-Yu Tsai, Shan-Yin Wu, Ching-Ming Yen, Chia-Jui Chuang, Bin-Fay Chang, Jang-Yang Clin. Cancer Res. 17:7116-26 21668414 Pubmed 2011 A drug targeting only p110? can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types Jamieson, Stephen Flanagan, Jack U Kolekar, Sharada Buchanan, Christina Kendall, Jackie D Lee, Woo-Jeong Rewcastle, Gordon W Denny, William A Singh, Ripudaman Dickson, James Baguley, Bruce C Shepherd, Peter R Biochem. J. 438:53-62 20522708 Pubmed 2010 Phosphatidylinositol 3-kinase-? inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals Herman, Sarah E M Gordon, Amber L Wagner, Amy J Heerema, Nyla A Zhao, Weiqiang Flynn, Joseph M Jones, Jeffrey Andritsos, Leslie Puri, Kamal D Lannutti, Brian J Giese, Neill A Zhang, Xiaoli Wei, Lai Byrd, John C Johnson, Amy J Blood 116:2078-88 22802530 Pubmed 2012 The p110? and p110? isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis Utermark, Tamara Rao, Trisha Cheng, Hailing Wang, Qi Lee, Sang Hyun Wang, Zhigang C Iglehart, J Dirk Roberts, Thomas M Muller, William J Zhao, Jean J Genes Dev. 26:1573-86 21368164 Pubmed 2012 Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors Chakrabarty, Anindita Sánchez, Violeta Kuba, María G Rinehart, Cammie Arteaga, Carlos L Proc. Natl. Acad. Sci. U.S.A. 109:2718-23 15834429 Pubmed 2005 PI 3-kinase p110beta: a new target for antithrombotic therapy Jackson, Shaun P Schoenwaelder, Simone M Goncalves, Isaac Nesbitt, Warwick S Yap, Cindy L Wright, Christine E Kenche, Vijaya Anderson, Karen E Dopheide, Sacha M Yuan, Yuping Sturgeon, Sharelle A Prabaharan, Hishani Thompson, Philip E Smith, Gregg D Shepherd, Peter R Daniele, Nathalie Kulkarni, S Abbott, Belinda Saylik, Dilek Jones, Catherine Lu, Lucy Giuliano, Simon Hughan, Sascha C Angus, James A Robertson, Alan D Salem, Hatem H Nat. Med. 11:507-14 19644473 Pubmed 2009 Targeting the phosphoinositide 3-kinase pathway in cancer Liu, Pixu Cheng, Hailing Roberts, Thomas M Zhao, Jean J Nat Rev Drug Discov 8:627-44 18829560 Pubmed 2008 NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations Serra, Violeta Markman, Ben Scaltriti, Maurizio Eichhorn, Pieter J A Valero, Vanesa Guzman, Marta Botero, Maria Luisa Llonch, Elisabeth Atzori, Francesco Di Cosimo, Serena Maira, Michel Garcia-Echeverria, Carlos Parra, Josep Lluis Arribas, Joaquin Baselga, J Cancer Res. 68:8022-30 22588880 Pubmed 2012 Functional characterization of an isoform-selective inhibitor of PI3K-p110? as a potential anticancer agent Ni, Jing Liu, Qingsong Xie, Shaozhen Carlson, Coby Von, Thanh Vogel, Kurt Riddle, Steve Benes, Cyril Eck, Michael Roberts, Thomas Gray, Nathanael S Zhao, Jean Cancer Discov 2:425-33 19411071 Pubmed 2009 Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941 Junttila, TT Akita, Robert W Parsons, K Fields, C Lewis Phillips, GD Friedman, LS Sampath, D Sliwkowski, MX Cancer Cell 15:429-40 16647110 Pubmed 2006 A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling Knight, Zachary A Gonzalez, Beatriz Feldman, Morri E Zunder, Eli R Goldenberg, David D Williams, Olusegun Loewith, Robbie Stokoe, David Balla, Andras Toth, Balazs Balla, Tamas Weiss, William A Williams, RL Shokat, Kevan M Cell 125:733-47 20713702 Pubmed 2010 Cancer-derived mutations in the regulatory subunit p85alpha of phosphoinositide 3-kinase function through the catalytic subunit p110alpha Sun, Minghao Hillmann, Petra Hofmann, Bianca T Hart, Jonathan R Vogt, Peter K Proc. Natl. Acad. Sci. U.S.A. 107:15547-52 21317208 Pubmed 2011 Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide Prasad, Gautam Sottero, Theo Yang, Xiaodong Mueller, Sabine James, C David Weiss, William A Polley, Mei-Yin Ozawa, Tomoko Berger, Mitchel S Aftab, Dana T Prados, Michael D Haas-Kogan, Daphne A Neuro-oncology 13:384-92 18606717 Pubmed 2008 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 Maira, Sauveur-Michel Stauffer, Frédéric Brueggen, Josef Furet, Pascal Schnell, Christian Fritsch, Christine Brachmann, Saskia Chène, Patrick De Pover, Alain Schoemaker, Kevin Fabbro, D Gabriel, Daniela Simonen, Marjo Murphy, Leon Finan, Peter Sellers, William García-Echeverría, Carlos Mol. Cancer Ther. 7:1851-63 22188813 Pubmed 2012 Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor Maira, Sauveur-Michel Pecchi, Sabina Huang, Alan Burger, Matthew Knapp, Mark Sterker, Dario Schnell, Christian Guthy, Daniel Nagel, Tobi Wiesmann, M Brachmann, Saskia Fritsch, Christine Dorsch, Marion Chène, Patrick Shoemaker, Kevin De Pover, Alain Menezes, Daniel Martiny-Baron, Georg Fabbro, D Wilson, Christopher J Schlegel, Robert Hofmann, F García-Echeverría, Carlos Sellers, William R Voliva, Charles F Mol. Cancer Ther. 11:317-28 8657148 Pubmed 1996 Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction Wymann, Matthias Bulgarelli-Leva, Ginette Zvelebil, Marketa Pirola, Luciano Vanhaesebroeck, Bart Waterfield, Michael Panayotou, George Mol. Cell. Biol. 16:1722-33