Phosphatidylinositol may be phosphorylated at either 3- or 4- positions on the inositol ring by PI 3-kinases or PI 4-kinases, respectively.

Phosphatidylinositol 3-kinases

Phosphatidylinositol 3-kinases (PI3K, provisional nomenclature) catalyse the introduction of a phosphate into the 3-position of phosphatidylinositol (PI), phosphatidylinositol 4-phosphate (PIP) or phosphatidylinositol 4,5-bisphosphate (PIP₂). There is evidence that PI3K can also phosphorylate serine/threonine residues on proteins. In addition to the classes described below, further serine/threonine protein kinases, including ATM (Q13315) and mTOR (P42345), have been described to phosphorylate phosphatidylinositol and have been termed PI3K-related kinases. Structurally, PI3Ks have common motifs of at least one C2, calcium-binding domain and helical domains, alongside structurally-conserved catalytic domains. Wortmannin and LY 294002 are widely-used inhibitors of PI3K activities. Wortmannin is irreversible and shows modest selectivity between Class I and Class II PI3K, while LY294002 is reversible and selective for Class I compared to Class II PI3K.

Class I PI3Ks (EC 2.7.1.153) phosphorylate phosphatidylinositol 4,5-bisphosphate to generate phosphatidylinositol 3,4,5-trisphosphate and are heterodimeric, matching catalytic and regulatory subunits. Class IA PI3Ks include p110α, p110β and p110δ catalytic subunits, with predominantly p85 and p55 regulatory subunits. The single catalytic subunit that forms Class IB PI3K is p110γ. Class IA PI3Ks are more associated with receptor tyrosine kinase pathways, while the Class IB PI3K is linked more with GPCR signalling.

Class II PI3Ks (EC 2.7.1.154) phosphorylate phosphatidylinositol to generate phosphatidylinositol 3-phosphate (and possibly phosphatidylinositol 4-phosphate to generate phosphatidylinositol 3,4-bisphosphate). Three monomeric members exist, PI3K-C2α, β and β, and include Ras-binding, Phox homology and two C2 domains.

The only class III PI3K isoform (EC 2.7.1.137) is a heterodimer formed of a catalytic subunit (VPS34) and regulatory subunit (VPS15).

Phosphatidylinositol 4-kinases

Phosphatidylinositol 4-kinases (EC 2.7.1.67) generate phosphatidylinositol 4-phosphate and may be divided into higher molecular weight type III and lower molecular weight type II forms.

Wortmannin also inhibits type III phosphatidylinositol 4-kinases and polo-like kinase [14]. PIK93 also inhibits PI 3-kinases [10]. Adenosine activates adenosine receptors.

* Key recommended reading is highlighted with an asterisk

Bauer TM, Patel MR, Infante JR. (2015) Targeting PI3 kinase in cancer. Pharmacol Ther, 146: 53-60. [PMID:25240910]

* Goncalves MD, Hopkins BD, Cantley LC. (2018) Phosphatidylinositol 3-Kinase, Growth Disorders, and Cancer. N Engl J Med, 379 (21): 2052-2062. [PMID:30462943]

Mayer IA, Arteaga CL. (2016) The PI3K/AKT Pathway as a Target for Cancer Treatment. Annu Rev Med, 67: 11-28. [PMID:26473415]

* Raphael J, Desautels D, Pritchard KI, Petkova E, Shah PS. (2018) Phosphoinositide 3-kinase inhibitors in advanced breast cancer: A systematic review and meta-analysis. Eur J Cancer, 91: 38-46. [PMID:29331750]

Singh P, Dar MS, Dar MJ. (2016) p110α and p110β isoforms of PI3K signaling: are they two sides of the same coin?. FEBS Lett, 590 (18): 3071-82. [PMID:27552098]

* Wang D, Zhou W, Chen J, Wei W. (2019) Upstream regulators of phosphoinositide 3-kinase and their role in diseases. J Cell Physiol, 234 (9): 14460-14472. [PMID:30710358]

Zhu J, Hou T, Mao X. (2015) Discovery of selective phosphatidylinositol 3-kinase inhibitors to treat hematological malignancies. Drug Discov Today, 20 (8): 988-94. [PMID:25857437]

1. Balla A, Kim YJ, Varnai P, Szentpetery Z, Knight Z, Shokat KM, Balla T. (2008) Maintenance of hormone-sensitive phosphoinositide pools in the plasma membrane requires phosphatidylinositol 4-kinase IIIalpha. Mol Biol Cell, 19 (2): 711-21. [PMID:18077555]

2. Bergamini G, Bell K, Shimamura S, Werner T, Cansfield A, Müller K, Perrin J, Rau C, Ellard K, Hopf C et al.. (2012) A selective inhibitor reveals PI3Kγ dependence of T(H)17 cell differentiation. Nat Chem Biol, 8 (6): 576-82. [PMID:22544264]

3. Cano C, Saravanan K, Bailey C, Bardos J, Curtin NJ, Frigerio M, Golding BT, Hardcastle IR, Hummersone MG, Menear KA et al.. (2013) 1-substituted (Dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-ones endowed with dual DNA-PK/PI3-K inhibitory activity. J Med Chem, 56 (16): 6386-401. [PMID:23855836]

4. Folkes AJ, Ahmadi K, Alderton WK, Alix S, Baker SJ, Box G, Chuckowree IS, Clarke PA, Depledge P, Eccles SA et al.. (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 . J Med Chem, 51 (18): 5522-32. [PMID:18754654]

5. Furet P, Guagnano V, Fairhurst RA, Imbach-Weese P, Bruce I, Knapp M, Fritsch C, Blasco F, Blanz J, Aichholz R et al.. (2013) Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation. Bioorg Med Chem Lett, 23 (13): 3741-8. [PMID:23726034]

6. Gehrmann T, Gülkan H, Suer S, Herberg FW, Balla A, Vereb G, Mayr GW, Heilmeyer Jr LM. (1999) Functional expression and characterisation of a new human phosphatidylinositol 4-kinase PI4K230. Biochim Biophys Acta, 1437 (3): 341-56. [PMID:10101268]

7. Hausser A, Storz P, Märtens S, Link G, Toker A, Pfizenmaier K. (2005) Protein kinase D regulates vesicular transport by phosphorylating and activating phosphatidylinositol-4 kinase IIIbeta at the Golgi complex. Nat Cell Biol, 7 (9): 880-6. [PMID:16100512]

8. Hayakawa M, Kawaguchi K, Kaizawa H, Koizumi T, Ohishi T, Yamano M, Okada M, Ohta M, Tsukamoto S, Raynaud FI et al.. (2007) Synthesis and biological evaluation of sulfonylhydrazone-substituted imidazo[1,2-a]pyridines as novel PI3 kinase p110alpha inhibitors. Bioorg Med Chem, 15 (17): 5837-44. [PMID:17601739]

9. Knight SD, Adams ND, Burgess JL, Chaudhari AM, Darcy MG, Donatelli CA, Luengo JI, Newlander KA, Parrish CA, Ridgers LH et al.. (2010) Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin. ACS Med Chem Lett, 1 (1): 39-43. [PMID:24900173]

10. Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O, Loewith R, Stokoe D, Balla A, Toth B et al.. (2006) A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell, 125 (4): 733-47. [PMID:16647110]

11. Lannutti BJ, Meadows SA, Herman SE, Kashishian A, Steiner B, Johnson AJ, Byrd JC, Tyner JW, Loriaux MM, Deininger M et al.. (2011) CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood, 117 (2): 591-4. [PMID:20959606]

12. Liu KK, Zhu J, Smith GL, Yin MJ, Bailey S, Chen JH, Hu Q, Huang Q, Li C, Li QJ et al.. (2011) Highly Selective and Potent Thiophenes as PI3K Inhibitors with Oral Antitumor Activity. ACS Med Chem Lett, 2 (11): 809-13. [PMID:24900269]

13. Liu Q, Wang J, Kang SA, Thoreen CC, Hur W, Ahmed T, Sabatini DM, Gray NS. (2011) Discovery of 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective, and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancer. J Med Chem, 54 (5): 1473-80. [PMID:21322566]

14. Liu Y, Shreder KR, Gai W, Corral S, Ferris DK, Rosenblum JS. (2005) Wortmannin, a widely used phosphoinositide 3-kinase inhibitor, also potently inhibits mammalian polo-like kinase. Chem Biol, 12 (1): 99-107. [PMID:15664519]

15. Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, Brachmann S, Chène P, De Pover A, Schoemaker K et al.. (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. Mol Cancer Ther, 7 (7): 1851-63. [PMID:18606717]

16. Markman B, Tabernero J, Krop I, Shapiro GI, Siu L, Chen LC, Mita M, Melendez Cuero M, Stutvoet S, Birle D et al.. (2012) Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors. Ann Oncol, 23 (9): 2399-408. [PMID:22357447]

17. Meyers R, Cantley LC. (1997) Cloning and characterization of a wortmannin-sensitive human phosphatidylinositol 4-kinase. J Biol Chem, 272 (7): 4384-90. [PMID:9020160]

18. Nylander S, Kull B, Björkman JA, Ulvinge JC, Oakes N, Emanuelsson BM, Andersson M, Skärby T, Inghardt T, Fjellström O et al.. (2012) Human target validation of phosphoinositide 3-kinase (PI3K)β: effects on platelets and insulin sensitivity, using AZD6482 a novel PI3Kβ inhibitor. J Thromb Haemost, 10 (10): 2127-36. [PMID:22906130]

19. Palanki MS, Dneprovskaia E, Doukas J, Fine RM, Hood J, Kang X, Lohse D, Martin M, Noronha G, Soll RM et al.. (2007) Discovery of 3,3'-(2,4-diaminopteridine-6,7-diyl)diphenol as an isozyme-selective inhibitor of PI3K for the treatment of ischemia reperfusion injury associated with myocardial infarction. J Med Chem, 50 (18): 4279-94. [PMID:17685602]

20. Raynaud FI, Eccles SA, Patel S, Alix S, Box G, Chuckowree I, Folkes A, Gowan S, De Haven Brandon A, Di Stefano F et al.. (2009) Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941. Mol Cancer Ther, 8 (7): 1725-38. [PMID:19584227]

21. Sutherlin DP, Bao L, Berry M, Castanedo G, Chuckowree I, Dotson J, Folks A, Friedman L, Goldsmith R, Gunzner J et al.. (2011) Discovery of a potent, selective, and orally available class I phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) kinase inhibitor (GDC-0980) for the treatment of cancer. J Med Chem, 54 (21): 7579-87. [PMID:21981714]

22. Tai AW, Bojjireddy N, Balla T. (2011) A homogeneous and nonisotopic assay for phosphatidylinositol 4-kinases. Anal Biochem, 417 (1): 97-102. [PMID:21704602]

23. Venkatesan AM, Dehnhardt CM, Delos Santos E, Chen Z, Dos Santos O, Ayral-Kaloustian S, Khafizova G, Brooijmans N, Mallon R, Hollander I et al.. (2010) Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor. J Med Chem, 53 (6): 2636-45. [PMID:20166697]

24. Wu P, Hu Y. (2012) Small molecules targeting phosphoinositide 3-kinases. Medchemcomm, 3 (11): 1337-1355. DOI: 10.1039/C2MD20044A

25. Yaguchi S, Fukui Y, Koshimizu I, Yoshimi H, Matsuno T, Gouda H, Hirono S, Yamazaki K, Yamori T. (2006) Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor. J Natl Cancer Inst, 98 (8): 545-56. [PMID:16622124]

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