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Current Topics in Medicinal Chemistry

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ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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Review Article

Isoform-Selective PI3K Inhibitors for Various Diseases

Author(s): Rammohan R.Y. Bheemanaboina*

Volume 20, Issue 12, 2020

Page: [1074 - 1092] Pages: 19

DOI: 10.2174/1568026620666200106141717

Price: $65

Abstract

Phosphoinositide 3-kinases (PI3Ks) are a family of ubiquitously distributed lipid kinases that control a wide variety of intracellular signaling pathways. Over the years, PI3K has emerged as an attractive target for the development of novel pharmaceuticals to treat cancer and various other diseases. In the last five years, four of the PI3K inhibitors viz. Idelalisib, Copanlisib, Duvelisib, and Alpelisib were approved by the FDA for the treatment of different types of cancer and several other PI3K inhibitors are currently under active clinical development. So far clinical candidates are non-selective kinase inhibitors with various off-target liabilities due to cross-reactivities. Hence, there is a need for the discovery of isoform-selective inhibitors with improved efficacy and fewer side-effects. The development of isoform-selective inhibitors is essential to reveal the unique functions of each isoform and its corresponding therapeutic potential. Although the clinical effect and relative benefit of pan and isoformselective inhibition will ultimately be determined, with the development of drug resistance and the demand for next-generation inhibitors, it will continue to be of great significance to understand the potential mechanism of isoform-selectivity. Because of the important role of type I PI3K family members in various pathophysiological processes, isoform-selective PI3K inhibitors may ultimately have considerable efficacy in a wide range of human diseases. This review summarizes the progress of isoformselective PI3K inhibitors in preclinical and early clinical studies for anticancer and other various diseases.

Keywords: PI3K, Isoform-selective, Cancer, Inflammation, Thrombosis, Cardiovascular.

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[1]
Cantley, L.C. The phosphoinositide 3-kinase pathway. Science, 2002, 296(5573), 1655-1657.
[http://dx.doi.org/10.1126/science.296.5573.1655] [PMID: 12040186]
[2]
Fruman, D.A.; Chiu, H.; Hopkins, B.D.; Bagrodia, S.; Cantley, L.C.; Abraham, R.T. The PI3K pathway in human disease. Cell, 2017, 170(4), 605-635.
[http://dx.doi.org/10.1016/j.cell.2017.07.029] [PMID: 28802037]
[3]
Marone, R.; Cmiljanovic, V.; Giese, B.; Wymann, M.P. Targeting phosphoinositide 3-kinase: moving towards therapy. Biochim. Biophys. Acta, 2008, 1784(1), 159-185.
[http://dx.doi.org/10.1016/j.bbapap.2007.10.003] [PMID: 17997386]
[4]
Garces, A.E.; Stocks, M.J. Class 1 PI3K clinical candidates and recent inhibitor design strategies: a medicinal chemistry perspective. J. Med. Chem., 2019, 62(10), 4815-4850.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01492] [PMID: 30582807]
[5]
Jackson, S.P.; Schoenwaelder, S.M.; Goncalves, I.; Nesbitt, W.S.; Yap, C.L.; Wright, C.E.; Kenche, V.; Anderson, K.E.; Dopheide, S.M.; Yuan, Y.; Sturgeon, S.A.; Prabaharan, H.; Thompson, P.E.; Smith, G.D.; Shepherd, P.R.; Daniele, N.; Kulkarni, S.; Abbott, B.; Saylik, D.; Jones, C.; Lu, L.; Giuliano, S.; Hughan, S.C.; Angus, J.A.; Robertson, A.D.; Salem, H.H. PI 3-kinase p110β: a new target for antithrombotic therapy. Nat. Med., 2005, 11(5), 507-514.
[http://dx.doi.org/10.1038/nm1232] [PMID: 15834429]
[6]
Jackson, S.F.; Schoenwaelder, S.M. Type I phosphoinositide 3-kinases: potential antithrombotic targets? Cell. Mol. Life Sci., 2006, 63(10), 1085-1090.
[http://dx.doi.org/10.1007/s00018-006-6001-2] [PMID: 16649145]
[7]
Lucas, C.L.; Kuehn, H.S.; Zhao, F.; Niemela, J.E.; Deenick, E.K.; Palendira, U.; Avery, D.T.; Moens, L.; Cannons, J.L.; Biancalana, M.; Stoddard, J.; Ouyang, W.; Frucht, D.M.; Rao, V.K.; Atkinson, T.P.; Agharahimi, A.; Hussey, A.A.; Folio, L.R.; Olivier, K.N.; Fleisher, T.A.; Pittaluga, S.; Holland, S.M.; Cohen, J.I.; Oliveira, J.B.; Tangye, S.G.; Schwartzberg, P.L.; Lenardo, M.J.; Uzel, G. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nat. Immunol., 2014, 15(1), 88-97.
[http://dx.doi.org/10.1038/ni.2771] [PMID: 24165795]
[8]
Angulo, I.; Vadas, O.; Garçon, F.; Banham-Hall, E.; Plagnol, V.; Leahy, T.R.; Baxendale, H.; Coulter, T.; Curtis, J.; Wu, C.; Blake-Palmer, K.; Perisic, O.; Smyth, D.; Maes, M.; Fiddler, C.; Juss, J.; Cilliers, D.; Markelj, G.; Chandra, A.; Farmer, G.; Kielkowska, A.; Clark, J.; Kracker, S.; Debré, M.; Picard, C.; Pellier, I.; Jabado, N.; Morris, J.A.; Barcenas-Morales, G.; Fischer, A.; Stephens, L.; Hawkins, P.; Barrett, J.C.; Abinun, M.; Clatworthy, M.; Durandy, A.; Doffinger, R.; Chilvers, E.R.; Cant, A.J.; Kumararatne, D.; Okkenhaug, K.; Williams, R.L.; Condliffe, A.; Nejentsev, S. Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. Science, 2013, 342(6160), 866-871.
[http://dx.doi.org/10.1126/science.1243292] [PMID: 24136356]
[9]
Kaneda, M.M.; Messer, K.S.; Ralainirina, N.; Li, H.; Leem, C.J.; Gorjestani, S.; Woo, G.; Nguyen, A.V.; Figueiredo, C.C.; Foubert, P.; Schmid, M.C.; Pink, M.; Winkler, D.G.; Rausch, M.; Palombella, V.J.; Kutok, J.; McGovern, K.; Frazer, K.A.; Wu, X.; Karin, M.; Sasik, R.; Cohen, E.E.; Varner, J.A. PI3Kγ is a molecular switch that controls immune suppression. Nature, 2016, 539(7629), 437-442.
[http://dx.doi.org/10.1038/nature19834] [PMID: 27642729]
[10]
Hawkins, P.T.; Stephens, L.R. PI3K signalling in inflammation. Biochim. Biophys. Acta, 2015, 1851(6), 882-897.
[http://dx.doi.org/10.1016/j.bbalip.2014.12.006] [PMID: 25514767]
[11]
Perry, M.W.D.; Abdulai, R.; Mogemark, M.; Petersen, J.; Thomas, M.J.; Valastro, B.; Westin Eriksson, A. Evolution of PI3Kγ and δ inhibitors for inflammatory and autoimmune diseases. J. Med. Chem., 2019, 62(10), 4783-4814.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01298] [PMID: 30582813]
[12]
Cushing, T.D.; Metz, D.P.; Whittington, D.A.; McGee, L.R. PI3Kδ and PI3Kγ as targets for autoimmune and inflammatory diseases. J. Med. Chem., 2012, 55(20), 8559-8581.
[http://dx.doi.org/10.1021/jm300847w] [PMID: 22924688]
[13]
Gulluni, F.; De Santis, M.C.; Margaria, J.P.; Martini, M.; Hirsch, E. Class II PI3K functions in cell biology and disease. Trends Cell Biol., 2019, 29(4), 339-359.
[http://dx.doi.org/10.1016/j.tcb.2019.01.001] [PMID: 30691999]
[14]
Falasca, M.; Hamilton, J.R.; Selvadurai, M.; Sundaram, K.; Adamska, A.; Thompson, P.E. Class II phosphoinositide 3-kinases as novel drug targets. J. Med. Chem., 2017, 60(1), 47-65.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00963] [PMID: 27644332]
[15]
Krag, C.; Malmberg, E.K.; Salcini, A.E. PI3KC2α, a class II PI3K, is required for dynamin-independent internalization pathways. J. Cell Sci., 2010, 123(Pt 24), 4240-4250.
[http://dx.doi.org/10.1242/jcs.071712] [PMID: 21081650]
[16]
Russo, A.; Okur, M.N.; Bosland, M.; O’Bryan, J.P. Phosphatidylinositol 3-kinase, class 2 beta (PI3KC2β) isoform contributes to neuroblastoma tumorigenesis. Cancer Lett., 2015, 359(2), 262-268.
[http://dx.doi.org/10.1016/j.canlet.2015.01.026] [PMID: 25622909]
[17]
Chikh, A.; Ferro, R.; Abbott, J.J.; Piñeiro, R.; Buus, R.; Iezzi, M.; Ricci, F.; Bergamaschi, D.; Ostano, P.; Chiorino, G.; Lattanzio, R.; Broggini, M.; Piantelli, M.; Maffucci, T.; Falasca, M. Class II phosphoinositide 3-kinase C2β regulates a novel signaling pathway involved in breast cancer progression. Oncotarget, 2016, 7(14), 18325-18345.
[http://dx.doi.org/10.18632/oncotarget.7761] [PMID: 26934321]
[18]
Boller, D.; Doepfner, K.T.; De Laurentiis, A.; Guerreiro, A.S.; Marinov, M.; Shalaby, T.; Depledge, P.; Robson, A.; Saghir, N.; Hayakawa, M.; Kaizawa, H.; Koizumi, T.; Ohishi, T.; Fattet, S.; Delattre, O.; Schweri-Olac, A.; Höland, K.; Grotzer, M.A.; Frei, K.; Spertini, O.; Waterfield, M.D.; Arcaro, A. Targeting PI3KC2β impairs proliferation and survival in acute leukemia, brain tumours and neuroendocrine tumours. Anticancer Res., 2012, 32(8), 3015-3027.
[PMID: 22843869]
[19]
Falasca, M.; Maffucci, T. Regulation and cellular functions of class II phosphoinositide 3-kinases. Biochem. J., 2012, 443(3), 587-601.
[http://dx.doi.org/10.1042/BJ20120008] [PMID: 22507127]
[20]
Herman, P.K.; Emr, S.D. Characterization of VPS34, a gene required for vacuolar protein sorting and vacuole segregation in Saccharomyces cerevisiae. Mol. Cell. Biol., 1990, 10(12), 6742-6754.
[http://dx.doi.org/10.1128/MCB.10.12.6742] [PMID: 2247081]
[21]
Backer, J.M. The regulation and function of Class III PI3Ks: novel roles for Vps34. Biochem. J., 2008, 410(1), 1-17.
[http://dx.doi.org/10.1042/BJ20071427] [PMID: 18215151]
[22]
Greenwell, I.B.; Ip, A.; Cohen, J.B. PI3K Inhibitors: understanding toxicity mechanisms and management. Oncology (Williston Park), 2017, 31(11), 821-828.
[PMID: 29179250]
[23]
Curigliano, G.; Shah, R.R. Safety and tolerability of phosphatidylinositol-3-Kinase (PI3K) inhibitors in oncology. Drug Saf., 2019, 42(2), 247-262.
[http://dx.doi.org/10.1007/s40264-018-0778-4] [PMID: 30649751]
[24]
Koyasu, S. The role of PI3K in immune cells. Nat. Immunol., 2003, 4(4), 313-319.
[http://dx.doi.org/10.1038/ni0403-313] [PMID: 12660731]
[25]
Ghigo, A.; Hirsch, E. Isoform selective phosphoinositide 3-kinase gamma and delta inhibitors and their therapeutic potential. Recent Pat. Inflamm. Allergy Drug Discov., 2008, 2(1), 1-10.
[http://dx.doi.org/10.2174/187221308783399270] [PMID: 19075988]
[26]
Zhu, J.; Ke, K.; Xu, L.; Jin, J. Theoretical studies on the selectivity mechanisms of PI3Kδ inhibition with marketed idelalisib and its derivatives by 3D-QSAR, molecular docking, and molecular dynamics simulation. J. Mol. Model., 2019, 25(8), 242.
[http://dx.doi.org/10.1007/s00894-019-4129-x] [PMID: 31338599]
[27]
Li, T.; Wang, G. Computer-aided targeting of the PI3K/Akt/mTOR pathway: toxicity reduction and therapeutic opportunities. Int. J. Mol. Sci., 2014, 15(10), 18856-18891.
[http://dx.doi.org/10.3390/ijms151018856] [PMID: 25334061]
[28]
Sabbah, D.A.; Vennerstrom, J.L.; Zhong, H. Docking studies on isoform-specific inhibition of phosphoinositide-3-kinases. J. Chem. Inf. Model., 2010, 50(10), 1887-1898.
[http://dx.doi.org/10.1021/ci1002679] [PMID: 20866085]
[29]
Pinson, J.A.; Schmidt-Kittler, O.; Zhu, J.; Jennings, I.G.; Kinzler, K.W.; Vogelstein, B.; Chalmers, D.K.; Thompson, P.E. Thiazolidinedione-based PI3Kα inhibitors: an analysis of biochemical and virtual screening methods. ChemMedChem, 2011, 6(3), 514-522.
[http://dx.doi.org/10.1002/cmdc.201000467] [PMID: 21360822]
[30]
Zheng, Z.; Amran, S.I.; Thompson, P.E.; Jennings, I.G. Isoform-selective inhibition of phosphoinositide 3-kinase: identification of a new region of nonconserved amino acids critical for p110α inhibition. Mol. Pharmacol., 2011, 80(4), 657-664.
[http://dx.doi.org/10.1124/mol.111.072546] [PMID: 21778304]
[31]
Wang, X.; Ding, J.; Meng, L.H. PI3K isoform-selective inhibitors: next-generation targeted cancer therapies. Acta Pharmacol. Sin., 2015, 36(10), 1170-1176.
[http://dx.doi.org/10.1038/aps.2015.71] [PMID: 26364801]
[32]
Liu, P.; Cheng, H.; Roberts, T.M.; Zhao, J.J. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. Drug Discov., 2009, 8(8), 627-644.
[http://dx.doi.org/10.1038/nrd2926] [PMID: 19644473]
[33]
Thomas, D.; Powell, J.A.; Vergez, F.; Segal, D.H.; Nguyen, N.Y.; Baker, A.; Teh, T.C.; Barry, E.F.; Sarry, J.E.; Lee, E.M.; Nero, T.L.; Jabbour, A.M.; Pomilio, G.; Green, B.D.; Manenti, S.; Glaser, S.P.; Parker, M.W.; Lopez, A.F.; Ekert, P.G.; Lock, R.B.; Huang, D.C.; Nilsson, S.K.; Récher, C.; Wei, A.H.; Guthridge, M.A. Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription. Blood, 2013, 122(5), 738-748.
[http://dx.doi.org/10.1182/blood-2012-08-447441] [PMID: 23775716]
[34]
Duong, H.Q.; Yi, Y.W.; Kang, H.J.; Hong, Y.B.; Tang, W.; Wang, A.; Seong, Y.S.; Bae, I. Inhibition of NRF2 by PIK-75 augments sensitivity of pancreatic cancer cells to gemcitabine. Int. J. Oncol., 2014, 44(3), 959-969.
[http://dx.doi.org/10.3892/ijo.2013.2229] [PMID: 24366069]
[35]
Kim, O.; Jeong, Y.; Lee, H.; Hong, S.S.; Hong, S. Design and synthesis of imidazopyridine analogues as inhibitors of phosphoinositide 3-kinase signaling and angiogenesis. J. Med. Chem., 2011, 54(7), 2455-2466.
[http://dx.doi.org/10.1021/jm101582z] [PMID: 21388141]
[36]
Rumman, M.; Jung, K.H.; Fang, Z.; Yan, H.H.; Son, M.K.; Kim, S.J.; Kim, J.; Park, J.H.; Lim, J.H.; Hong, S.; Hong, S.S. HS-173, a novel PI3K inhibitor suppresses EMT and metastasis in pancreatic cancer. Oncotarget, 2016, 7(47), 78029-78047.
[http://dx.doi.org/10.18632/oncotarget.12871] [PMID: 27793006]
[37]
Lee, H.; Jung, K.H.; Jeong, Y.; Hong, S.; Hong, S.S. HS-173, a novel phosphatidylinositol 3-kinase (PI3K) inhibitor, has anti-tumor activity through promoting apoptosis and inhibiting angiogenesis. Cancer Lett., 2013, 328(1), 152-159.
[http://dx.doi.org/10.1016/j.canlet.2012.08.020] [PMID: 22929971]
[38]
Yun, S.M.; Jung, K.H.; Lee, H.; Son, M.K.; Seo, J.H.; Yan, H.H.; Park, B.H.; Hong, S.; Hong, S.S. Synergistic anticancer activity of HS-173, a novel PI3K inhibitor in combination with Sorafenib against pancreatic cancer cells. Cancer Lett., 2013, 331(2), 250-261.
[http://dx.doi.org/10.1016/j.canlet.2013.01.007] [PMID: 23340175]
[39]
Son, M.K.; Ryu, Y.L.; Jung, K.H.; Lee, H.; Lee, H.S.; Yan, H.H.; Park, H.J.; Ryu, J.K.; Suh, J.K.; Hong, S.; Hong, S.S. HS-173, a novel PI3K inhibitor, attenuates the activation of hepatic stellate cells in liver fibrosis. Sci. Rep., 2013, 3, 3470.
[http://dx.doi.org/10.1038/srep03470] [PMID: 24326778]
[40]
Jessen; K. A.; Kessler; L.; Kucharski; J.; Guo; X.; Staunton; J.; Elia; M.; Janes; M.; Lan; L.; Wang; S.; Stewart; J.; Darjania; L.; Li; L.; Chan; K.; Martin; M.; Ren; P.; Fruman; D.; Rommel; C.; Liu, Y. Abstract 4501: INK1117: a potent and orally efficacious PI3Kα-selective inhibitor for the treatment of cancer. Cancer Res., 2011, 71, 4501.
[41]
Juric, D.; de Bono, J.S.; LoRusso, P.M.; Nemunaitis, J.; Heath, E.I.; Kwak, E.L.; Macarulla Mercadé, T.; Geuna, E.; Jose de Miguel-Luken, M.; Patel, C.; Kuida, K.; Sankoh, S.; Westin, E.H.; Zohren, F.; Shou, Y.; Tabernero, J. A first-in-human, phase I, dose-escalation study of TAK-117, a selective PI3Kalpha isoform inhibitor, in patients with advanced solid malignancies. Clin. Cancer Res., 2017, 23(17), 5015-5023.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-2888] [PMID: 28490463]
[42]
Patel, C.G.; Rangachari, L.; Patti, M.; Griffin, C.; Shou, Y.; Venkatakrishnan, K. Characterizing the sources of pharmacokinetic variability for TAK-117 (Serabelisib), an investigational phosphoinositide 3-kinase alpha inhibitor: a clinical biopharmaceutics study to inform development strategy. Clin. Pharmacol. Drug Dev., 2019, 8(5), 637-646.
[http://dx.doi.org/10.1002/cpdd.613] [PMID: 30168905]
[43]
Jamieson, S.; Flanagan, J.U.; Kolekar, S.; Buchanan, C.; Kendall, J.D.; Lee, W.J.; Rewcastle, G.W.; Denny, W.A.; Singh, R.; Dickson, J.; Baguley, B.C.; Shepherd, P.R. A drug targeting only p110α can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types. Biochem. J., 2011, 438(1), 53-62.
[http://dx.doi.org/10.1042/BJ20110502] [PMID: 21668414]
[44]
Smith, G.C.; Ong, W.K.; Rewcastle, G.W.; Kendall, J.D.; Han, W.; Shepherd, P.R. Effects of acutely inhibiting PI3K isoforms and mTOR on regulation of glucose metabolism in vivo. Biochem. J., 2012, 442(1), 161-169.
[http://dx.doi.org/10.1042/BJ20111913] [PMID: 22142257]
[45]
Furet, P.; Guagnano, V.; Fairhurst, R.A.; Imbach-Weese, P.; Bruce, I.; Knapp, M.; Fritsch, C.; Blasco, F.; Blanz, J.; Aichholz, R.; Hamon, J.; Fabbro, D.; Caravatti, G. Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation. Bioorg. Med. Chem. Lett., 2013, 23(13), 3741-3748.https://www.fda.gov/news-events/press-announcements/fda-approves-first-pi3k-inhibitor-breast-cancer
[http://dx.doi.org/10.1016/j.bmcl.2013.05.007] [PMID: 23726034]
[46]
Fritsch, C.; Huang, A.; Chatenay-Rivauday, C.; Schnell, C.; Reddy, A.; Liu, M.; Kauffmann, A.; Guthy, D.; Erdmann, D.; De Pover, A.; Furet, P.; Gao, H.; Ferretti, S.; Wang, Y.; Trappe, J.; Brachmann, S.M.; Maira, S.M.; Wilson, C.; Boehm, M.; Garcia-Echeverria, C.; Chene, P.; Wiesmann, M.; Cozens, R.; Lehar, J.; Schlegel, R.; Caravatti, G.; Hofmann, F.; Sellers, W.R. Characterization of the novel and specific PI3Kα inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials. Mol. Cancer Ther., 2014, 13(5), 1117-1129.
[http://dx.doi.org/10.1158/1535-7163.MCT-13-0865] [PMID: 24608574]
[47]
Ndubaku, C.O.; Heffron, T.P.; Staben, S.T.; Baumgardner, M.; Blaquiere, N.; Bradley, E.; Bull, R.; Do, S.; Dotson, J.; Dudley, D.; Edgar, K.A.; Friedman, L.S.; Goldsmith, R.; Heald, R.A.; Kolesnikov, A.; Lee, L.; Lewis, C.; Nannini, M.; Nonomiya, J.; Pang, J.; Price, S.; Prior, W.W.; Salphati, L.; Sideris, S.; Wallin, J.J.; Wang, L.; Wei, B.; Sampath, D.; Olivero, A.G. Discovery of 2-3-[2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl-2-methylpropanamide (GDC-0032): a β-sparing phosphoinositide 3-kinase inhibitor with high unbound exposure and robust in vivo antitumor activity. J. Med. Chem., 2013, 56(11), 4597-4610.
[http://dx.doi.org/10.1021/jm4003632] [PMID: 23662903]
[48]
Juric, D.; Krop, I.; Ramanathan, R.K.; Wilson, T.R.; Ware, J.A.; Sanabria Bohorquez, S.M.; Savage, H.M.; Sampath, D.; Salphati, L.; Lin, R.S.; Jin, H.; Parmar, H.; Hsu, J.Y.; Von Hoff, D.D.; Baselga, J. Phase I dose-escalation study of Taselisib, an oral PI3K inhibitor, in patients with advanced solid tumors. Cancer Discov., 2017, 7(7), 704-715.
[http://dx.doi.org/10.1158/2159-8290.CD-16-1080] [PMID: 28331003]
[49]
Zumsteg, Z.S.; Morse, N.; Krigsfeld, G.; Gupta, G.; Higginson, D.S.; Lee, N.Y.; Morris, L.; Ganly, I.; Shiao, S.L.; Powell, S.N.; Chung, C.H.; Scaltriti, M.; Baselga, J. Taselisib (GDC-0032), a potent β-sparing small molecule inhibitor of PI3K, radiosensitizes head and neck squamous carcinomas containing activating PIK3CA alterations. Clin. Cancer Res., 2016, 22(8), 2009-2019.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-2245] [PMID: 26589432]
[50]
Heffron, T.P.; Heald, R.A.; Ndubaku, C.; Wei, B.; Augistin, M.; Do, S.; Edgar, K.; Eigenbrot, C.; Friedman, L.; Gancia, E.; Jackson, P.S.; Jones, G.; Kolesnikov, A.; Lee, L.B.; Lesnick, J.D.; Lewis, C.; McLean, N.; Mörtl, M.; Nonomiya, J.; Pang, J.; Price, S.; Prior, W.W.; Salphati, L.; Sideris, S.; Staben, S.T.; Steinbacher, S.; Tsui, V.; Wallin, J.; Sampath, D.; Olivero, A.G. The Rational Design of Selective Benzoxazepin Inhibitors of the α-Isoform of Phosphoinositide 3-Kinase Culminating in the Identification of (S)-2-((2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxy)propanamide (GDC-0326). J. Med. Chem., 2016, 59(3), 985-1002.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01483] [PMID: 26741947]
[51]
Soler, A.; Figueiredo, A.M.; Castel, P.; Martin, L.; Monelli, E.; Angulo-Urarte, A.; Milà-Guasch, M.; Viñals, F.; Baselga, J.; Casanovas, O.; Graupera, M. Therapeutic benefit of selective inhibition of p110α PI3-Kinase in pancreatic neuroendocrine tumors. Clin. Cancer Res., 2016, 22(23), 5805-5817.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-3051] [PMID: 27225693]
[52]
Yadav, R.R.; Guru, S.K.; Joshi, P.; Mahajan, G.; Mintoo, M.J.; Kumar, V.; Bharate, S.S.; Mondhe, D.M.; Vishwakarma, R.A.; Bhushan, S.; Bharate, S.B. 6-Aryl substituted 4-(4-cyanomethyl) phenylamino quinazolines as a new class of isoform-selective PI3K-alpha inhibitors. Eur. J. Med. Chem., 2016, 122, 731-743.
[http://dx.doi.org/10.1016/j.ejmech.2016.07.006] [PMID: 27479483]
[53]
Vishwakarma, R.A.; Bharate, S.B.; Bhushan, S.; Yadav, R.R.; Guru, S.K.; Joshi, P. 6-Aryl-4-phenylamino-quinazoline analogs as phosphoinositide-3-kinase inhibitors. U.S. Patent WO2015/ 128873A1. 2015..
[54]
Bharate, S.B.; Bhushan, S.; Mohammed, S.; Guru, S.K.; Bharate, S.S.; Kumar, V.; Mahajan, G.; Mintoo, M.J.; Mondhe, D.M.; Vishwakarma, R. Fused pyrimidines as isoform selective phosphoinositide-3-kinase-alpha inhibitors and process for preparation thereof. U. S. patent WO2017090058A1. 2017.
[55]
Yang, T.; Meoli, D.F.; Moslehi, J.; Roden, D.M. Inhibition of the α-subunit of phosphoinositide 3-kinase in heart increases late sodium current and is arrhythmogenic. J. Pharmacol. Exp. Ther., 2018, 365(3), 460-466.
[http://dx.doi.org/10.1124/jpet.117.246157] [PMID: 29563327]
[56]
Ghigo, A.; Morello, F.; Perino, A.; Hirsch, E. Therapeutic applications of PI3K inhibitors in cardiovascular diseases. Future Med. Chem., 2013, 5(4), 479-492.
[http://dx.doi.org/10.4155/fmc.13.11] [PMID: 23495693]
[57]
Holy, E.W.; Jakob, P.; Eickner, T.; Camici, G.G.; Beer, J.H.; Akhmedov, A.; Sternberg, K.; Schmitz, K-P.; Lüscher, T.F.; Tanner, F.C. PI3K/p110α inhibition selectively interferes with arterial thrombosis and neointima formation, but not re-endothelialization: potential implications for drug-eluting stent design. Eur. Heart J., 2014, 35(12), 808-820.
[http://dx.doi.org/10.1093/eurheartj/eht496] [PMID: 24334406]
[58]
Laurent, P-A.; Hechler, B.; Solinhac, R.; Ragab, A.; Cabou, C.; Anquetil, T.; Severin, S.; Denis, C.V.; Mangin, P.H.; Vanhaesebroeck, B.; Payrastre, B.; Gratacap, M-P. Impact of PI3Kα (phosphoinositide 3-kinase alpha) inhibition on hemostasis and thrombosis. Arterioscler. Thromb. Vasc. Biol., 2018, 38(9), 2041-2053.
[http://dx.doi.org/10.1161/ATVBAHA.118.311410] [PMID: 30354258]
[59]
Rossello, X.; Riquelme, J.A.; He, Z.; Taferner, S.; Vanhaesebroeck, B.; Davidson, S.M.; Yellon, D.M. The role of PI3Kα isoform in cardioprotection. Basic Res. Cardiol., 2017, 112(6), 66.
[http://dx.doi.org/10.1007/s00395-017-0657-7] [PMID: 29043508]
[60]
Dagia, N.M.; Agarwal, G.; Kamath, D.V.; Chetrapal-Kunwar, A.; Gupte, R.D.; Jadhav, M.G.; Dadarkar, S.S.; Trivedi, J.; Kulkarni-Almeida, A.A.; Kharas, F.; Fonseca, L.C.; Kumar, S.; Bhonde, M.R. A preferential p110α/γ PI3K inhibitor attenuates experimental inflammation by suppressing the production of proinflammatory mediators in a NF-kappaB-dependent manner. Am. J. Physiol. Cell Physiol., 2010, 298(4), C929-C941.
[http://dx.doi.org/10.1152/ajpcell.00461.2009] [PMID: 20089935]
[61]
Jude, J.A.; Tirumurugaan, K.G.; Kang, B.N.; Panettieri, R.A.; Walseth, T.F.; Kannan, M.S. Regulation of CD38 expression in human airway smooth muscle cells: role of class I phosphatidylinositol 3 kinases. Am. J. Respir. Cell Mol. Biol., 2012, 47(4), 427-435.
[http://dx.doi.org/10.1165/rcmb.2012-0025OC] [PMID: 22556157]
[62]
Ni, J.; Liu, Q.; Xie, S.; Carlson, C.; Von, T.; Vogel, K.; Riddle, S.; Benes, C.; Eck, M.; Roberts, T.; Gray, N.; Zhao, J. Functional characterization of an isoform-selective inhibitor of PI3K-p110β as a potential anticancer agent. Cancer Discov., 2012, 2(5), 425-433.
[http://dx.doi.org/10.1158/2159-8290.CD-12-0003] [PMID: 22588880]
[63]
Jackson, S.P.; Schoenwaelder, S.M. Antithrombotic phosphoinositide 3-kinase β inhibitors in humans: a ‘shear’ delight! J. Thromb. Haemost., 2012, 10(10), 2123-2126.
[http://dx.doi.org/10.1111/j.1538-7836.2012.04912.x] [PMID: 22943292]
[64]
Nylander, S.; Kull, B.; Björkman, J.A.; Ulvinge, J.C.; Oakes, N.; Emanuelsson, B.M.; Andersson, M.; Skärby, T.; Inghardt, T.; Fjellström, O.; Gustafsson, D. Human target validation of phosphoinositide 3-kinase (PI3K)β: effects on platelets and insulin sensitivity, using AZD6482 a novel PI3Kβ inhibitor. J. Thromb. Haemost., 2012, 10(10), 2127-2136.
[http://dx.doi.org/10.1111/j.1538-7836.2012.04898.x] [PMID: 22906130]
[65]
Pinson, J.A.; Zheng, Z.; Miller, M.S.; Chalmers, D.K.; Jennings, I.G.; Thompson, P.E. L-Aminoacyl-triazine derivatives are isoform-selective PI3Kβ inhibitors that target non-conserved Asp862 of PI3Kβ. ACS Med. Chem. Lett., 2013, 4(2), 206-210.
[http://dx.doi.org/10.1021/ml300336j] [PMID: 23795239]
[66]
Zheng, Z.; Pinson, J.A.; Mountford, S.J.; Orive, S.; Schoenwaelder, S.M.; Shackleford, D.; Powell, A.; Nelson, E.M.; Hamilton, J.R.; Jackson, S.P.; Jennings, I.G.; Thompson, P.E. Discovery and antiplatelet activity of a selective PI3Kβ inhibitor (MIPS-9922). Eur. J. Med. Chem., 2016, 122, 339-351.
[http://dx.doi.org/10.1016/j.ejmech.2016.06.010] [PMID: 27387421]
[67]
Yap, T.A.; Bjerke, L.; Clarke, P.A.; Workman, P. Drugging PI3K in cancer: refining targets and therapeutic strategies. Curr. Opin. Pharmacol., 2015, 23, 98-107.
[http://dx.doi.org/10.1016/j.coph.2015.05.016] [PMID: 26117819]
[68]
Mateo, J.; Ganji, G.; Lemech, C.; Burris, H.A.; Han, S.W.; Swales, K.; Decordova, S.; DeYoung, M.P.; Smith, D.A.; Kalyana-Sundaram, S.; Wu, J.; Motwani, M.; Kumar, R.; Tolson, J.M.; Rha, S.Y.; Chung, H.C.; Eder, J.P.; Sharma, S.; Bang, Y.J.; Infante, J.R.; Yan, L.; de Bono, J.S.; Arkenau, H.T. A first-time-in-human study of GSK2636771, a phosphoinositide 3 kinase beta-selective inhibitor, in patients with advanced solid tumors. Clin. Cancer Res., 2017, 23(19), 5981-5992.
[http://dx.doi.org/10.1158/1078-0432.CCR-17-0725] [PMID: 28645941]
[69]
Weigelt, B.; Warne, P.H.; Lambros, M.B.; Reis-Filho, J.S.; Downward, J. PI3K pathway dependencies in endometrioid endometrial cancer cell lines. Clin. Cancer Res., 2013, 19(13), 3533-3544.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-3815] [PMID: 23674493]
[70]
Tawbi, H.A-H.; Peng, W.; Milton, D.; Amaria, R.N.; Glitza, I.C.; Hwu, W-J.; Patel, S.P.; Wong, M.K.K.; Woodman, S.E.; Yee, C.; McQuade, J.L.; Tetzlaff, M.T.; Lazar, A.J.; Cain, S.; Burton, E.M.; Beumer, J.H.; Hwu, P.; Davies, M.A. Phase I/II study of the PI3Kβ inhibitor GSK2636771 in combination with pembrolizumab (P) in patients (pts) with PD-1 refractory metastatic melanoma (MM) and PTEN loss. J. Clin. Oncol., 2018, 36, TPS9596-TPS9596.
[http://dx.doi.org/10.1200/JCO.2018.36.15_suppl.TPS9596]
[71]
Certal, V.; Carry, J-C.; Halley, F.; Virone-Oddos, A.; Thompson, F.; Filoche-Rommé, B.; El-Ahmad, Y.; Karlsson, A.; Charrier, V.; Delorme, C.; Rak, A.; Abecassis, P-Y.; Amara, C.; Vincent, L.; Bonnevaux, H.; Nicolas, J-P.; Mathieu, M.; Bertrand, T.; Marquette, J-P.; Michot, N.; Benard, T.; Perrin, M-A.; Lemaitre, O.; Guerif, S.; Perron, S.; Monget, S.; Gruss-Leleu, F.; Doerflinger, G.; Guizani, H.; Brollo, M.; Delbarre, L.; Bertin, L.; Richepin, P.; Loyau, V.; Garcia-Echeverria, C.; Lengauer, C.; Schio, L. Discovery and optimization of pyrimidone indoline amide PI3Kβ inhibitors for the treatment of phosphatase and tensin homologue (PTEN)-deficient cancers. J. Med. Chem., 2014, 57(3), 903-920.
[http://dx.doi.org/10.1021/jm401642q] [PMID: 24387221]
[72]
Bonnevaux, H.; Lemaitre, O.; Vincent, L.; Levit, M.N.; Windenberger, F.; Halley, F.; Delorme, C.; Lengauer, C.; Garcia-Echeverria, C.; Virone-Oddos, A. Concomitant inhibition of PI3Kβ and BRAF or MEK in PTEN-deficient/BRAF-mutant melanoma treatment: Preclinical assessment of SAR260301 oral PI3Kβ-selective inhibitor. Mol. Cancer Ther., 2016, 15(7), 1460-1471.
[http://dx.doi.org/10.1158/1535-7163.MCT-15-0496] [PMID: 27196754]
[73]
Bédard, P.L.; Davies, M.A.; Kopetz, S.; Juric, D.; Shapiro, G.I.; Luke, J.J.; Spreafico, A.; Wu, B.; Castell, C.; Gomez, C.; Cartot-Cotton, S.; Mazuir, F.; Dubar, M.; Micallef, S.; Demers, B.; Flaherty, K.T. First-in-human trial of the PI3Kβ-selective inhibitor SAR260301 in patients with advanced solid tumors. Cancer, 2018, 124(2), 315-324.
[http://dx.doi.org/10.1002/cncr.31044] [PMID: 28976556]
[74]
Feng, C.; Sun, Y.; Ding, G.; Wu, Z.; Jiang, H.; Wang, L.; Ding, Q.; Wen, H. PI3Kβ inhibitor TGX221 selectively inhibits renal cell carcinoma cells with both VHL and SETD2 mutations and links multiple pathways. Sci. Rep., 2015, 5, 9465.
[http://dx.doi.org/10.1038/srep09465] [PMID: 25853938]
[75]
Yang, X.; Yang, J.A.; Liu, B.H.; Liao, J.M.; Yuan, F.E.; Tan, Y.Q.; Chen, Q.X. TGX-221 inhibits proliferation and induces apoptosis in human glioblastoma cells. Oncol. Rep., 2017, 38(5), 2836-2842.
[http://dx.doi.org/10.3892/or.2017.5991] [PMID: 29048665]
[76]
Karlsson, T.; Krakstad, C.; Tangen, I.L.; Hoivik, E.A.; Pollock, P.M.; Salvesen, H.B.; Lewis, A.E. Endometrial cancer cells exhibit high expression of p110β and its selective inhibition induces variable responses on PI3K signaling, cell survival and proliferation. Oncotarget, 2017, 8(3), 3881-3894.
[http://dx.doi.org/10.18632/oncotarget.13989] [PMID: 28002804]
[77]
Xu, P.F.; Yang, J.A.; Liu, J.H.; Yang, X.; Liao, J.M.; Yuan, F.E.; Liu, B.H.; Chen, Q.X. PI3Kβ inhibitor AZD6482 exerts antiproliferative activity and induces apoptosis in human glioblastoma cells. Oncol. Rep., 2019, 41(1), 125-132.
[PMID: 30542720]
[78]
Rowan, W.C.; Smith, J.L.; Affleck, K.; Amour, A. Targeting phosphoinositide 3-kinase δ for allergic asthma. Biochem. Soc. Trans., 2012, 40(1), 240-245.
[http://dx.doi.org/10.1042/BST20110665] [PMID: 22260698]
[79]
Sriskantharajah, S.; Hamblin, N.; Worsley, S.; Calver, A.R.; Hessel, E.M.; Amour, A. Targeting phosphoinositide 3-kinase δ for the treatment of respiratory diseases. Ann. N. Y. Acad. Sci., 2013, 1280, 35-39.
[http://dx.doi.org/10.1111/nyas.12039] [PMID: 23551101]
[80]
Stokes, C.A.; Condliffe, A.M. Phosphoinositide 3-kinase δ (PI3Kδ) in respiratory disease. Biochem. Soc. Trans., 2018, 46(2), 361-369.
[http://dx.doi.org/10.1042/BST20170467] [PMID: 29523773]
[81]
Coulter, T. I.; Chandra, A.; Bacon, C. M.; Babar, J.; Curtis, J.; Screaton, N.; Goodlad, J. R.; Farmer, G.; Steele, C. L.; Leahy, T. R.; Doffinger, R.; Baxendale, H.; Bernatoniene, J.; Edgar, J. D.; Longhurst, H. J.; Ehl, S.; Speckmann, C.; Grimbacher, B.; Sediva, A.; Milota, T.; Faust, S. N.; Williams, A. P.; Hayman, G.; Kucuk, Z. Y.; Hague, R.; French, P.; Brooker, R.; Forsyth, P.; Herriot, R.; Cancrini, C.; Palma, P.; Ariganello, P.; Conlon, N.; Feighery, C.; Gavin, P. J.; Jones, A.; Imai, K.; Ibrahim, M. A.; Markelj, G.; Abinun, M.; Rieux-Laucat, F.; Latour, S.; Pellier, I.; Fischer, A.; Touzot, F.; Casanova, J. L.; Durandy, A.; Burns, S. O.; Savic, S.; Kumararatne, D. S.; Moshous, D.; Kracker, S.; Vanhaesebroeck, B.; Okkenhaug, K.; Picard, C.; Nejentsev, S.; Condliffe, A. M.; Cant, A. J. J. Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome: A large patient cohort study. J. Allergy Clin. Immunol., 2017, 139(2), 597-606. e594.
[82]
U.S. Food and Drug Administration. Available from:. http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm406387.htm
[83]
Lannutti, B.J.; Meadows, S.A.; Herman, S.E.; Kashishian, A.; Steiner, B.; Johnson, A.J.; Byrd, J.C.; Tyner, J.W.; Loriaux, M.M.; Deininger, M.; Druker, B.J.; Puri, K.D.; Ulrich, R.G.; Giese, N.A. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood, 2011, 117(2), 591-594.
[http://dx.doi.org/10.1182/blood-2010-03-275305] [PMID: 20959606]
[84]
Sharman, J.P.; Coutre, S.E.; Furman, R.R.; Cheson, B.D.; Pagel, J.M.; Hillmen, P.; Barrientos, J.C.; Zelenetz, A.D.; Kipps, T.J.; Flinn, I.W.; Ghia, P.; Eradat, H.; Ervin, T.; Lamanna, N.; Coiffier, B.; Pettitt, A.R.; Ma, S.; Tausch, E.; Cramer, P.; Huang, J.; Mitra, S.; Hallek, M.; O’Brien, S.M.; Stilgenbauer, S. Final results of a randomized, phase III study of rituximab with or without idelalisib followed by open-label idelalisib in patients with relapsed chronic lymphocytic leukemia. J. Clin. Oncol., 2019, 37(16), 1391-1402.
[http://dx.doi.org/10.1200/JCO.18.01460] [PMID: 30995176]
[85]
Yang, Q.; Modi, P.; Newcomb, T.; Quéva, C.; Gandhi, V. Idelalisib: first-in-class PI3K delta inhibitor for the treatment of chronic lymphocytic leukemia, small lymphocytic leukemia, and follicular lymphoma. Clin. Cancer Res., 2015, 21(7), 1537-1542.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-2034] [PMID: 25670221]
[86]
Cheah, C.Y.; Fowler, N.H. Idelalisib in the management of lymphoma. Blood, 2016, 128(3), 331-336.
[http://dx.doi.org/10.1182/blood-2016-02-702761] [PMID: 27252232]
[87]
Burris, H.A., III; Flinn, I.W.; Patel, M.R.; Fenske, T.S.; Deng, C.; Brander, D.M.; Gutierrez, M.; Essell, J.H.; Kuhn, J.G.; Miskin, H.P.; Sportelli, P.; Weiss, M.S.; Vakkalanka, S.; Savona, M.R.; O’Connor, O.A. Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. Lancet Oncol., 2018, 19(4), 486-496.
[http://dx.doi.org/10.1016/S1470-2045(18)30082-2] [PMID: 29475723]
[88]
Barrientos, J.C. Can umbralisib bring PI3Kδ out of the shadows? Lancet Oncol., 2018, 19(4), 432-434.
[http://dx.doi.org/10.1016/S1470-2045(18)30154-2] [PMID: 29475725]
[89]
Lampson, B.L.; Brown, J.R. PI3Kδ-selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma. Expert Opin. Investig. Drugs, 2017, 26(11), 1267-1279.
[http://dx.doi.org/10.1080/13543784.2017.1384815] [PMID: 28945111]
[90]
Niemann, C.U.; Mora-Jensen, H.I.; Dadashian, E.L.; Krantz, F.; Covey, T.; Chen, S.S.; Chiorazzi, N.; Izumi, R.; Ulrich, R.; Lannutti, B.J.; Wiestner, A.; Herman, S.E.M. Combined BTK and PI3Kδ inhibition with acalabrutinib and ACP-319 improves survival and tumor control in CLL mouse model. Clin. Cancer Res., 2017, 23(19), 5814-5823.
[http://dx.doi.org/10.1158/1078-0432.CCR-17-0650] [PMID: 28645939]
[91]
Cushing, T.D.; Hao, X.; Shin, Y.; Andrews, K.; Brown, M.; Cardozo, M.; Chen, Y.; Duquette, J.; Fisher, B.; Gonzalez-Lopez de Turiso, F.; He, X.; Henne, K.R.; Hu, Y.L.; Hungate, R.; Johnson, M.G.; Kelly, R.C.; Lucas, B.; McCarter, J.D.; McGee, L.R.; Medina, J.C.; San Miguel, T.; Mohn, D.; Pattaropong, V.; Pettus, L.H.; Reichelt, A.; Rzasa, R.M.; Seganish, J.; Tasker, A.S.; Wahl, R.C.; Wannberg, S.; Whittington, D.A.; Whoriskey, J.; Yu, G.; Zalameda, L.; Zhang, D.; Metz, D.P. Discovery and in vivo evaluation of (S)-N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and related PI3Kδ inhibitors for inflammation and autoimmune disease. J. Med. Chem., 2015, 58(1), 480-511.
[http://dx.doi.org/10.1021/jm501624r] [PMID: 25469863]
[92]
Down, K.; Amour, A.; Baldwin, I.R.; Cooper, A.W.; Deakin, A.M.; Felton, L.M.; Guntrip, S.B.; Hardy, C.; Harrison, Z.A.; Jones, K.L.; Jones, P.; Keeling, S.E.; Le, J.; Livia, S.; Lucas, F.; Lunniss, C.J.; Parr, N.J.; Robinson, E.; Rowland, P.; Smith, S.; Thomas, D.A.; Vitulli, G.; Washio, Y.; Hamblin, J.N. Optimization of novel indazoles as highly potent and selective inhibitors of phosphoinositide 3-kinase δ for the treatment of respiratory disease. J. Med. Chem., 2015, 58(18), 7381-7399.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00767] [PMID: 26301626]
[93]
Wilson, R.; Templeton, A.; Leemereise, C.; Eames, R.; Banham-Hall, E.; Hessel, E.M.; Cahn, A. Safety, tolerability, and pharmacokinetics of a new formulation of Nemiralisib administered via a dry powder inhaler to healthy individuals. Clin. Ther., 2019, 41(6), 1214-1220.
[http://dx.doi.org/10.1016/j.clinthera.2019.04.008] [PMID: 31076203]
[94]
Cahn, A.; Hamblin, J.N.; Begg, M.; Wilson, R.; Dunsire, L.; Sriskantharajah, S.; Montembault, M.; Leemereise, C.N.; Galinanes-Garcia, L.; Watz, H.; Kirsten, A.M.; Fuhr, R.; Hessel, E.M. Safety, pharmacokinetics and dose-response characteristics of GSK2269557, an inhaled PI3Kδ inhibitor under development for the treatment of COPD. Pulm. Pharmacol. Ther., 2017, 46, 69-77.
[http://dx.doi.org/10.1016/j.pupt.2017.08.008] [PMID: 28823947]
[95]
Hoegenauer, K.; Soldermann, N.; Zécri, F.; Strang, R.S.; Graveleau, N.; Wolf, R.M.; Cooke, N.G.; Smith, A.B.; Hollingworth, G.J.; Blanz, J.; Gutmann, S.; Rummel, G.; Littlewood-Evans, A.; Burkhart, C. Discovery of CDZ173 (Leniolisib), representing a structurally novel class of PI3K delta-selective inhibitors. ACS Med. Chem. Lett., 2017, 8(9), 975-980.
[http://dx.doi.org/10.1021/acsmedchemlett.7b00293] [PMID: 28947947]
[96]
Rao, V.K.; Webster, S.; Dalm, V.A.S.H.; Šedivá, A.; van Hagen, P.M.; Holland, S.; Rosenzweig, S.D.; Christ, A.D.; Sloth, B.; Cabanski, M.; Joshi, A.D.; de Buck, S.; Doucet, J.; Guerini, D.; Kalis, C.; Pylvaenaeinen, I.; Soldermann, N.; Kashyap, A.; Uzel, G.; Lenardo, M.J.; Patel, D.D.; Lucas, C.L.; Burkhart, C. Effective “activated PI3Kδ syndrome”-targeted therapy with the PI3Kδ inhibitor leniolisib. Blood, 2017, 130(21), 2307-2316.
[http://dx.doi.org/10.1182/blood-2017-08-801191] [PMID: 28972011]
[97]
Evans, C.A.; Liu, T.; Lescarbeau, A.; Nair, S.J.; Grenier, L.; Pradeilles, J.A.; Glenadel, Q.; Tibbitts, T.; Rowley, A.M.; DiNitto, J.P.; Brophy, E.E.; O’Hearn, E.L.; Ali, J.A.; Winkler, D.G.; Goldstein, S.I.; O’Hearn, P.; Martin, C.M.; Hoyt, J.G.; Soglia, J.R.; Cheung, C.; Pink, M.M.; Proctor, J.L.; Palombella, V.J.; Tremblay, M.R.; Castro, A.C. Discovery of a selective phosphoinositide-3-kinase (PI3K)-γ Inhibitor (IPI-549) as an immuno-oncology clinical candidate. ACS Med. Chem. Lett., 2016, 7(9), 862-867.
[http://dx.doi.org/10.1021/acsmedchemlett.6b00238] [PMID: 27660692]
[98]
Takeda, A.J.; Maher, T.J.; Zhang, Y.; Lanahan, S.M.; Bucklin, M.L.; Compton, S.R.; Tyler, P.M.; Comrie, W.A.; Matsuda, M.; Olivier, K.N.; Pittaluga, S.; McElwee, J.J.; Long Priel, D.A.; Kuhns, D.B.; Williams, R.L.; Mustillo, P.J.; Wymann, M.P.; Koneti Rao, V.; Lucas, C.L. Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology. Nat. Commun., 2019, 10(1), 4364.
[http://dx.doi.org/10.1038/s41467-019-12311-5] [PMID: 31554793]
[99]
Bergamini, G.; Bell, K.; Shimamura, S.; Werner, T.; Cansfield, A.; Müller, K.; Perrin, J.; Rau, C.; Ellard, K.; Hopf, C.; Doce, C.; Leggate, D.; Mangano, R.; Mathieson, T.; O’Mahony, A.; Plavec, I.; Rharbaoui, F.; Reinhard, F.; Savitski, M.M.; Ramsden, N.; Hirsch, E.; Drewes, G.; Rausch, O.; Bantscheff, M.; Neubauer, G. A selective inhibitor reveals PI3Kγ dependence of T(H)17 cell differentiation. Nat. Chem. Biol., 2012, 8(6), 576-582.
[http://dx.doi.org/10.1038/nchembio.957] [PMID: 22544264]
[100]
Bell, K.; Sunose, M.; Ellard, K.; Cansfield, A.; Taylor, J.; Miller, W.; Ramsden, N.; Bergamini, G.; Neubauer, G. SAR studies around a series of triazolopyridines as potent and selective PI3Kγ inhibitors. Bioorg. Med. Chem. Lett., 2012, 22(16), 5257-5263.
[http://dx.doi.org/10.1016/j.bmcl.2012.06.049] [PMID: 22819766]
[101]
Jin, M.; Zhou, Q.; Lee, E.; Dan, S.; Duan, H.Q.; Kong, D. AS252424, a PI3Kγ inhibitor, downregulates inflammatory responsiveness in mouse bone marrow-derived mast cells. Inflammation, 2014, 37(4), 1254-1260.
[http://dx.doi.org/10.1007/s10753-014-9852-y] [PMID: 24577728]
[102]
Graves, B.M.; Simerly, T.; Li, C.; Williams, D.L.; Wondergem, R. Phosphoinositide-3-kinase/akt - dependent signaling is required for maintenance of [Ca(2+)](i), I(Ca), and Ca(2+) transients in HL-1 cardiomyocytes. J. Biomed. Sci., 2012, 19, 59.
[http://dx.doi.org/10.1186/1423-0127-19-59] [PMID: 22715995]
[103]
Tyagi, S.; Sharma, S.; Budhiraja, R.D. Effect of phosphatidylinositol 3-kinase-γ inhibitor CAY10505 in hypertension, and its associated vascular endothelium dysfunction in rats. Can. J. Physiol. Pharmacol., 2012, 90(7), 881-885.
[http://dx.doi.org/10.1139/y2012-089] [PMID: 22731503]
[104]
Camps, M.; Rückle, T.; Ji, H.; Ardissone, V.; Rintelen, F.; Shaw, J.; Ferrandi, C.; Chabert, C.; Gillieron, C.; Françon, B.; Martin, T.; Gretener, D.; Perrin, D.; Leroy, D.; Vitte, P.A.; Hirsch, E.; Wymann, M.P.; Cirillo, R.; Schwarz, M.K.; Rommel, C. Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nat. Med., 2005, 11(9), 936-943.
[http://dx.doi.org/10.1038/nm1284] [PMID: 16127437]
[105]
Hohenester, S.; Gates, A.; Wimmer, R.; Beuers, U.; Anwer, M.S.; Rust, C.; Webster, C.R. Phosphatidylinositol-3-kinase p110γ contributes to bile salt-induced apoptosis in primary rat hepatocytes and human hepatoma cells. J. Hepatol., 2010, 53(5), 918-926.
[http://dx.doi.org/10.1016/j.jhep.2010.05.015] [PMID: 20675006]
[106]
Hasan, A.M.; Mourtada-Maarabouni, M.; Hameed, M.S.; Williams, G.T.; Dent, G. Phosphoinositide 3-kinase gamma mediates chemotactic responses of human eosinophils to platelet-activating factor. Int. Immunopharmacol., 2010, 10(9), 1017-1021.
[http://dx.doi.org/10.1016/j.intimp.2010.05.014] [PMID: 20685403]
[107]
Kim, M.S.; Rådinger, M.; Gilfillan, A.M. The multiple roles of phosphoinositide 3-kinase in mast cell biology. Trends Immunol., 2008, 29(10), 493-501.
[http://dx.doi.org/10.1016/j.it.2008.07.004] [PMID: 18775670]
[108]
Yuan, X.; Wu, H.; Bu, H.; Zhou, J.; Zhang, H. Targeting the immunity protein kinases for immuno-oncology. Eur. J. Med. Chem., 2019, 163, 413-427.
[http://dx.doi.org/10.1016/j.ejmech.2018.11.072] [PMID: 30530193]
[109]
Rodrigues, D.A.; Sagrillo, F.S.; Fraga, C.A.M. Duvelisib: a 2018 novel FDA-approved small molecule inhibiting phosphoinositide 3-kinases. Pharmaceuticals (Basel), 2019, 12(2), 69.
[http://dx.doi.org/10.3390/ph12020069] [PMID: 31064155]
[110]
Blair, H.A. Duvelisib: first global approval. Drugs, 2018, 78(17), 1847-1853.
[http://dx.doi.org/10.1007/s40265-018-1013-4] [PMID: 30430368]
[111]
Winkler, D.G.; Faia, K.L.; DiNitto, J.P.; Ali, J.A.; White, K.F.; Brophy, E.E.; Pink, M.M.; Proctor, J.L.; Lussier, J.; Martin, C.M.; Hoyt, J.G.; Tillotson, B.; Murphy, E.L.; Lim, A.R.; Thomas, B.D.; Macdougall, J.R.; Ren, P.; Liu, Y.; Li, L.S.; Jessen, K.A.; Fritz, C.C.; Dunbar, J.L.; Porter, J.R.; Rommel, C.; Palombella, V.J.; Changelian, P.S.; Kutok, J.L. PI3K-δ and PI3K-γ inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models. Chem. Biol., 2013, 20(11), 1364-1374.
[http://dx.doi.org/10.1016/j.chembiol.2013.09.017] [PMID: 24211136]
[112]
Vakkalanka, S.; Viswanadha, S.; Gaudio, E.; Zucca, E.; Bertoni, F.; Bernasconi, E.; Rossi, D.; Stathis, A. Dual PI3Kδ/γ inhibition by RP6530 induces apoptosis and cytotoxicity In B-lymphoma cells. Blood, 2013, 122(21), 4411-4411.
[http://dx.doi.org/10.1182/blood.V122.21.4411.4411]
[113]
Rhizen Pharmaceuticals, S.A. Available on, https://www. globenewswire.com/news-release/2018/04/13/1471290/0/en/Rhizen-Pharmaceuticals-S-A-receives-FDA-Fast-Track-Designation-for-Tenalisib-RP6530-a-highly-selective-dual-PI3K-delta-gamma-inhibitor-for-the-treatment-of-patients-with-relapsed-a.html
[114]
Jia, H.; Dai, G.; Su, W.; Xiao, K.; Weng, J.; Zhang, Z.; Wang, Q.; Yuan, T.; Shi, F.; Zhang, Z.; Chen, W.; Sai, Y.; Wang, J.; Li, X.; Cai, Y.; Yu, J.; Ren, P.; Venable, J.; Rao, T.; Edwards, J.P.; Bembenek, S.D. Discovery, optimization, and evaluation of potent and highly selective PI3Kγ–PI3Kδ dual inhibitors. J. Med. Chem., 2019, 62(10), 4936-4948.
[http://dx.doi.org/10.1021/acs.jmedchem.8b02014] [PMID: 31033293]

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