PI3K inhibitors block PI3K catalytic activity

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Reaction [binding]
Homo sapiens
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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.
Literature References
PubMed ID Title Journal Year
22802530 The p110? and p110? isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis

Roberts, TM, Utermark, T, Muller, WJ, Cheng, H, Lee, SH, Wang, ZC, Rao, T, Iglehart, JD, Zhao, JJ, Wang, Q

Genes Dev. 2012
19411071 Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941

Junttila, TT, Fields, C, Sliwkowski, MX, Lewis Phillips, GD, Sampath, D, Friedman, LS, Parsons, K, Akita, RW

Cancer Cell 2009
19644473 Targeting the phosphoinositide 3-kinase pathway in cancer

Roberts, TM, Cheng, H, Liu, P, Zhao, JJ

Nat Rev Drug Discov 2009
21976531 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

Chuang, BF, Tsai, SY, Chang, KY, Chang, JY, Yen, CJ, Wu, CM

Clin. Cancer Res. 2011
18606717 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

Furet, P, De Pover, A, Brachmann, S, Finan, P, Chène, P, Fabbro, D, García-Echeverría, C, Maira, SM, Murphy, L, Gabriel, D, Schnell, C, Schoemaker, K, Fritsch, C, Brueggen, J, Simonen, M, Sellers, W, Stauffer, F

Mol. Cancer Ther. 2008
18829560 NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations

Arribas, J, Maira, M, Baselga, J, Guzman, M, Parra, JL, Eichhorn, PJ, Atzori, F, Botero, ML, Serra, V, Valero, V, Markman, B, Di Cosimo, S, Llonch, E, Garcia-Echeverria, C, Scaltriti, M

Cancer Res. 2008
18754654 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

Valenti, M, Workman, P, Depledge, P, Alix, S, Hancox, TC, Kugendradas, A, Baker, SJ, Box, G, Chuckowree, IS, Eccles, SA, Alderton, WK, Ultsch, MH, Pang, J, Clarke, PA, Saghir, N, Patel, S, Zhyvoloup, A, Wiesmann, C, Wan, NC, Moore, P, Wallweber, HJ, Zvelebil, MJ, Pergl-Wilson, GH, Raynaud, FI, Ahmadi, K, Lensun, L, Hayes, A, Salphati, L, Robson, A, Olivero, AG, Shuttleworth, SJ, Sohal, S, Friedman, LS, Folkes, AJ

J. Med. Chem. 2008
15834429 PI 3-kinase p110beta: a new target for antithrombotic therapy

Thompson, PE, Goncalves, I, Lu, L, Anderson, KE, Jones, C, Schoenwaelder, SM, Kulkarni, S, Kenche, V, Jackson, SP, Salem, HH, Sturgeon, SA, Wright, CE, Yap, CL, Hughan, SC, Yuan, Y, Prabaharan, H, Daniele, N, Smith, GD, Giuliano, S, Nesbitt, WS, Dopheide, SM, Shepherd, PR, Saylik, D, Abbott, B, Robertson, AD, Angus, JA

Nat. Med. 2005
21368164 Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors

Kuba, MG, Arteaga, CL, Rinehart, C, Sánchez, V, Chakrabarty, A

Proc. Natl. Acad. Sci. U.S.A. 2012
21317208 Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide

Weiss, WA, Yang, X, Polley, MY, Haas-Kogan, DA, James, CD, Sottero, T, Prados, MD, Prasad, G, Ozawa, T, Berger, MS, Aftab, DT, Mueller, S

Neuro-oncology 2011
8657148 Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction

Wymann, MP, Bulgarelli-Leva, G, Pirola, L, Waterfield, MD, Vanhaesebroeck, B, Zvelebil, MJ, Panayotou, G

Mol. Cell. Biol. 1996
16647110 A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling

Shokat, KM, Williams, O, Gonzalez, B, Williams, RL, Stokoe, D, Loewith, R, Balla, A, Weiss, WA, Balla, T, Zunder, ER, Feldman, ME, Knight, ZA, Toth, B, Goldenberg, DD

Cell 2006
22588880 Functional characterization of an isoform-selective inhibitor of PI3K-p110? as a potential anticancer agent

Ni, J, Carlson, C, Zhao, J, Riddle, S, Xie, S, Roberts, T, Von, T, Vogel, K, Gray, NS, Eck, M, Benes, C, Liu, Q

Cancer Discov 2012
22188813 Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor

De Pover, A, Hofmann, F, Brachmann, S, Chène, P, Fabbro, D, Guthy, D, García-Echeverría, C, Martiny-Baron, G, Menezes, D, Shoemaker, K, Pecchi, S, Fritsch, C, Huang, A, Sellers, WR, Wiesmann, M, Voliva, CF, Dorsch, M, Maira, SM, Schnell, C, Sterker, D, Nagel, T, Wilson, CJ, Knapp, M, Burger, M, Schlegel, R

Mol. Cancer Ther. 2012
21668414 A drug targeting only p110? can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types

Singh, R, Kolekar, S, Shepherd, PR, Denny, WA, Flanagan, JU, Baguley, BC, Rewcastle, GW, Kendall, JD, Dickson, J, Jamieson, S, Lee, WJ, Buchanan, C

Biochem. J. 2011
20713702 Cancer-derived mutations in the regulatory subunit p85alpha of phosphoinositide 3-kinase function through the catalytic subunit p110alpha

Hofmann, BT, Hillmann, P, Vogt, PK, Sun, M, Hart, JR

Proc. Natl. Acad. Sci. U.S.A. 2010
20522708 Phosphatidylinositol 3-kinase-? inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals

Byrd, JC, Lannutti, BJ, Johnson, AJ, Andritsos, L, Zhang, X, Puri, KD, Heerema, NA, Wagner, AJ, Zhao, W, Jones, J, Giese, NA, Wei, L, Gordon, AL, Herman, SE, Flynn, JM

Blood 2010
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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