Review of research on dual PI3K-mTOR small molecular inhibitors

CHEN Ying; HAN Jinsong; WANG Chongqing; SONG Yunlong; ZHOU Yonggang; ZHU Ju

doi:10.3969/j.issn.1006-0111.2014.05.004

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Objective The phosphoinositide 3-kinase (PI3K) constituted an important family of lipid kinase enzymes that control a range of cellular proliferation, differentiation and apoptosis through their regulation of a network of signal transduction pathways, which had emerged as important therapeutic targets in the context of cancer and inflammation. Considerable progress had been made in the discovery and development of small molecular inhibitors targeting PI3K. Progress in dual PI3K-mTOR inhibitors, a number of which had entered early phase clinical trials over recent years was summarized.

Review of research on dual PI3K-mTOR small molecular inhibitors

1. Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China

2. Department of Pharmacy, No. 81 Hospital of PLA, Nanjing 210002, China

Received Date: 2013-03-18

Rev Recd Date: 2013-04-08

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Abstract: Objective The phosphoinositide 3-kinase (PI3K) constituted an important family of lipid kinase enzymes that control a range of cellular proliferation, differentiation and apoptosis through their regulation of a network of signal transduction pathways, which had emerged as important therapeutic targets in the context of cancer and inflammation. Considerable progress had been made in the discovery and development of small molecular inhibitors targeting PI3K. Progress in dual PI3K-mTOR inhibitors, a number of which had entered early phase clinical trials over recent years was summarized.

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[1]	Vivanco I, Sawyers CL, The phosphatidylinositol 3,kinase AKT pathway in human cancer[J]. Nat Rev Cancer, 2002,2(7):489-501.
[2]	Bjornsti MA, Houghton PJ, The TOR pathway:a target for cancer therapy[J]. Nat Rev Cancer, 2004,4(5):335-348.
[3]	Workman P, Clarke PA, Raynaud FI,et al.Drugging the PI3 kinome:from chemical tools to drugs in the clinic[J]. Cancer Res, 2010,70(6):2146-2157.
[4]	Denley A, Kang S, Karst U,et al.Oncogenic signaling of class I PI3K isoforms[J]. Oncogene, 2008, 27(18):2561-2574.
[5]	Falasca M, Maffucci T, Role of class Ⅱ phosphoinositide 3-kinase in cell signalling[J]. Biochem Soc Trans, 2007,35(Pt 2):211-214.
[6]	Guertin DA, Sabatini DM. Defining the role of mTOR in cancer[J]. Cancer Cell, 2007,12(1):9-22.
[7]	Bunney TD, Katan M.Phosphoinositide signalling in cancer:beyond PI3K and PTEN[J]. Nat Rev Cancer, 2010,10(5):342-352.
[8]	Bussink J, van der Kogel AJ, Kaanders JH, Activation of the PI3,K/AKT pathway and implications for radioresistance mechanisms in head and neck cancer[J]. Lancet Oncol, 2008,9(3):288-296.
[9]	Massion PP, Kuo WL, Stokoe D,et al. Genomic copy number analysis of non-small cell lung cancer using array comparative genomic hybridization:implications of the phosphatidylinositol 3-kinase pathway[J]. Cancer Res, 2002,62(13):3636-3640.
[10]	Sutherlin DP, Bao L, Berry M,et al. 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]. J Med Chem, 2011,54(21):7579-7587.
[11]	Wu P, Hu YZ.Small molecules targeting phosphoinositide 3-kinases[J]. Med Chem Comm, 2012,3(11):1337-1355.
[12]	Garlich JR, De P, Dey N,et al. A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity[J]. Cancer Res, 2008,68(1):206-215.
[13]	Ozbay T, Durden DL, Liu T,et al. In vitro evaluation of pan-PI3-kinase inhibitor SF1126 in trastuzumab-sensitive and trastuzumab-resistant HER2-over-expressing breast cancer cells[J]. Cancer Chemother Pharmacol, 2010,65(4):697-706.
[14]	Stauffer F, Maira SM, Furet P,et al. Imidazo[4,5-c]quinolines as inhibitors of the PI3K/PKB-pathway[J]. Bioorg Med Chem Lett, 2008,18(3):1027-1030.
[15]	Knight SD, Adams ND, Burgess JL,et al. Discovery of GSK2126458, a highly potent Inhibitor of PI3K and the mammalian target of rapamycin[J]. Acs Med Chem Lett, 2010,1(1):39-43.
[16]	Venkatesan AM, Dehnhardt CM, Delos SE,et al. 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]. J Med Chem, 2010,53(6):2636-2645.
[17]	Dehnhardt CM, Venkatesan AM, Delos SE,et al. Lead optimization of N-3-substituted 7-morpholinotriazolopyrimidines as dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors:discovery of PKI-402[J]. J Med Chem, 2010,53(2):798-810.
[18]	Mallon R, Feldberg LR, Lucas J, et al.Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor[J]. Clin Cancer Res, 2011,17(10):3193-3203.
[19]	Cheng HM, Bagrodia S, Bailey S,et al. Discovery of the highly potent PI3K/mTOR dual inhibitor PF-04691502 through structure based drug design[J]. Med Chem Comm, 2010,1(2):139-144.
[20]	Markman B, Tabernero J,Krop I,et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors[J]. Ann Oncol, 2012,23(9):2399-2408.
[21]	Heffron TP, Berry M, Castanedo G,et al. Identification of GNE-477, a potent and efficacious dual PI3K/mTOR inhibitor[J]. Bioorg Med Chem Lett, 2010,20(8):2408-2411.
[22]	Kashiyama T, Oda K, Ikeda Y,et al.Antitumor efficacy of DS-7423, a novel PI3K/mTOR dual inhibitor, in ovarian clear cell adenocarcinoma[J]. Eur J Cancer, 2012,48:110-111.

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Review of research on dual PI3K-mTOR small molecular inhibitors

doi: 10.3969/j.issn.1006-0111.2014.05.004

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