Ligand-Based Drug Design: Synthesis and Biological Evaluation of Substituted Benzoin Derivatives as Potential Antitumor Agents

Author(s): Dima A. Sabbah*, Ameerah H. Ibrahim, Wamidh H. Talib, Khalid M. Alqaisi, Kamal Sweidan, Sanaa K. Bardaweel, Ghassan A. Sheikha, Haizhen A. Zhong, Eveen Al-Shalabi, Reema A. Khalaf, Mohammad S. Mubarak.

Journal Name: Medicinal Chemistry

Volume 15 , Issue 4 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Background: Phosphoinositide 3-kinase α (PI3Kα) has emerged as a promising target for anticancer drug design.

Objectives: Target compounds were designed to investigate the effect of the p-OCH3 motifs on ligand/PI3Kα complex interaction and antiproliferative activity.

Methods: Synthesis of the proposed compounds, biological examination tests against human colon adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell lines, along with Glide docking studies.

Results: A series of 1,2-bis(4-methoxyphenyl)-2-oxoethyl benzoates was synthesized and characterized by means of FT-IR, 1H and 13C NMR, and by elemental analysis. Biological investigation demonstrated that the newly synthesized compounds exhibit antiproliferative activity in human colon adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell lines possibly via inhibition of PI3Kα and estrogen receptor alpha (ERα). Additionally, results revealed that these compounds exert selective inhibitory activity, induce apoptosis, and suppress VEGF production. Compound 3c exhibited promising antiproliferative activity in HCT-116 interrogating that hydrogen bond-acceptor mediates ligand/PI3Kα complex formation on m- position. Compounds 3e and 3i displayed high inhibitory activity in MCF-7 and T47D implying a wide cleft discloses the o-attachment. Furthermore, compound 3g exerted selective inhibitory activity against T47D. Glide docking studies against PI3Kα and ERα demonstrated that the series accommodate binding to PI3Kα and/or ERα.

Conclusion: The series exhibited a potential antitumor activity in human carcinoma cell lines encoding PI3Kα and/or ERα.

Keywords: PI3Kα; caspase-3, AKT, angiogenesis, glide docking, p-anisoin, HCT-116, MCF-7, T47D.

Vanhaesebroeck, B.; Waterfield, M.D. Signaling by distinct classes of phosphoinositide 3-kinases. Exp. Cell Res., 1999, 253(1), 239-254.
Vanhaesebroeck, B.; Guillermet-Guibert, J.; Graupera, M.; Bilanges, B. The emerging mechanisms of isoform-specific PI3K signalling. Nat. Rev. Mol. Cell Biol., 2010, 11(5), 329-341.
Vanhaesebroeck, B.; Stephens, L.; Hawkins, P. PI3K signalling: the path to discovery and understanding. Nat. Rev. Mol. Cell Biol., 2012, 13(3), 195-203.
Vivanco, I.; Sawyers, C.L. The phosphatidylinositol 3-kinase-AKT pathway in human cancer. Nat. Rev. Cancer, 2002, 2(7), 489-501.
Cantley, L.C. The phosphoinositide 3-kinase pathway. Science, 2002, 296(5573), 1655-1657.
Huang, C-H.; Mandelker, D.; Schmidt-Kittler, O.; Samuels, Y.; Velculescu, V.E.; Kinzler, K.W.; Vogelstein, B.; Gabelli, S.B.; Amzel, L.M. The structure of a human p110 alpha/p85 alpha complex elucidates the effects of oncogenic PI3K alpha mutations. Science, 2007, 318(5857), 1744-1748.
Samuels, Y.; Wang, Z.H.; Bardelli, A.; Silliman, N.; Ptak, J.; Szabo, S.; Yan, H.; Gazdar, A.; Powell, D.M.; Riggins, G.J.; Willson, J.K.V.; Markowitz, S.; Kinzler, K.W.; Vogelstein, B.; Velculescu, V.E. High frequency of mutations of the PIK3CA gene in human cancers. Science, 2004, 304(5670), 554-554.
Samuels, Y.; Diaz, L.A.; Schmidt-Kittler, O.; Cummins, J.M.; DeLong, L.; Cheong, I.; Rago, C.; Huso, D.L.; Lengauer, C.; Kinzler, K.W.; Vogelstein, B.; Velculescu, V.E. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell, 2005, 7(6), 561-573.
Zhao, L.; Vogt, P.K. Helical domain and kinase domain mutations in p110 alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc. Natl. Acad. Sci. USA, 2008, 105(7), 2652-2657.
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.
Miled, N.; Yan, Y.; Hon, W-C.; Perisic, O.; Zvelebil, M.; Inbar, Y.; Schneidman-Duhovny, D.; Wolfson, H.J.; Backer, J.M.; Williams, R.L. Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science, 2007, 317(5835), 239-242.
Cully, M.; You, H.; Levine, A.J.; Mak, T.W. Beyond PTEN mutations: The PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat. Rev. Cancer, 2006, 6(3), 184-192.
Carracedo, A.; Pandolfi, P.P. The PTEN-PI3K pathway: Of feedbacks and cross-talks. Oncogene, 2008, 27(41), 5527-5541.
Hayakawa, M.; Kaizawa, H.; Moritomo, H.; Koizumi, T.; Ohishi, T.; Okada, M.; Ohta, M.; Tsukamoto, S-i.; Parker, P.; Workman, P.; Waterfield, M. Synthesis and biological evaluation of 4-morpholino-2-phenylquinazolines and related derivatives as novel PI3 kinase p110 alpha inhibitors. Bioorg. Med. Chem., 2006, 14(20), 6847-6858.
Hayakawa, M.; Kaizawa, H.; Kawaguchi, K-i.; Ishikawa, N.; Koizumi, T.; Ohishi, T.; Yamano, M.; Okada, M.; Ohta, M.; Tsukamoto, S-i.; Raynaud, F.I.; Waterfield, M.D.; Parker, P.; Workman, P. Synthesis and biological evaluation of imidazo[1,2-a]pyridine derivatives as novel PI3 kinase p110 alpha inhibitors. Bioorg. Med. Chem., 2007, 15(1), 403-412.
Hayakawa, M.; Kaizawa, H.; Moritomo, H.; Koizumi, T.; Ohishi, T.; Yamano, M.; Okada, M.; Ohta, M.; Tsukamoto, S.; Raynaud, F.I.; Workman, P.; Waterfield, M.D.; Parker, P. Synthesis and biological evaluation of pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine derivatives as novel PI3 kinase p110alpha inhibitors. Bioorg. Med. Chem. Lett., 2007, 17(9), 2438-2442.
Hayakawa, M.; Kawaguchi, K-I.; Kaizawa, H.; Tomonobu, K.; Ohishi, T.; Yamano, M.; Okada, M.; Ohta, M.; Tsukamoto, S-i.; Raynaud, F.I.; Parker, P.; Workman, P.; Waterfield, M.D. Synthesis and biological evaluation of sulfonylhydrazone-substituted imidazo[1,2-a]pyridines as novel PI3 kinase p110 alpha inhibitors. Bioorg. Med. Chem., 2007, 15(17), 5837-5844.
Raynaud, F.I.; Eccles, S.; Clarke, P.A.; Hayes, A.; Nutley, B.; Alix, S.; Henley, A.; Di-Stefano, F.; Ahmad, Z.; Guillard, S.; Bjerke, L.M.; Kelland, L.; Valenti, M.; Patterson, L.; Gowan, S.; Brandon, A.D.H.; Hayakawa, M.; Kaizawa, H.; Koizumi, T.; Ohishi, T.; Patel, S.; Saghir, N.; Parker, P.; Waterfield, M.; Workman, P. Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases. Cancer Res., 2007, 67(12), 5840-5850.
Kendall, J.D.; Rewcastle, G.W.; Frederick, R.; Mawson, C.; Denny, W.A.; Marshall, E.S.; Baguley, B.C.; Chaussade, C.; Jackson, S.P.; Shepherd, P.R. Synthesis, biological evaluation and molecular modelling of sulfonohydrazides as selective PI3K p110 alpha inhibitors. Bioorg. Med. Chem., 2007, 15(24), 7677-7687.
Knight, S.D.; Adams, N.D.; Burgess, J.L.; Chaudhari, A.M.; Darcy, M.G.; Donatelli, C.A.; Luengo, J.I.; Newlander, K.A.; Parrish, C.A.; Ridgers, L.H.; Sarpong, M.A.; Schmidt, S.J.; Van Aller, G.S.; Carson, J.D.; Diamond, M.A.; Elkins, P.A.; Gardiner, C.M.; Garver, E.; Gilbert, S.A.; Gontarek, R.R.; Jackson, J.R.; Kershner, K.L.; Luo, L.; Raha, K.; Sherk, C.S.; Sung, C-M.; Sutton, D.; Tummino, P.J.; Wegrzyn, R.J.; Auger, K.R.; Dhanak, D. Discovery of GSK2126458, a highly potent inhibitor of PI3K and the mammalian target of Rapamycin. ACS Med. Chem. Lett., 2010, 1(1), 39-43.
Kendall, J.D.; Giddens, A.C.; Tsang, K.Y.; Frederick, R.; Marshall, E.S.; Singh, R.; Lill, C.L.; Lee, W-J.; Kolekar, S.; Chao, M.; Malik, A.; Yu, S.; Chaussade, C.; Buchanan, C.; Rewcastle, G.W.; Baguley, B.C.; Flanagan, J.U.; Jamieson, S.M.F.; Denny, W.A.; Shepherd, P.R. Novel pyrazolo[1,5-a]pyridines as p110α-selective PI3 kinase inhibitors: Exploring the benzenesulfonohydrazide SAR. Bioorg. Med. Chem., 2012, 20(1), 58-68.
Kendall, J.D.; O’Connor, P.D.; Marshall, A.J.; Frédérick, R.; Marshall, E.S.; Lill, C.L.; Lee, W.J.; Kolekar, S.; Chao, M.; Malik, A.; Yu, S.; Chaussade, C.; Buchanan, C.; Rewcastle, G.W.; Baguley, B.C.; Flanagan, J.U.; Jamieson, S.M.F.; Denny, W.A.; Shepherd, P.R. Discovery of pyrazolo[1,5-a]pyridines as p110α-selective PI3 kinase inhibitors. Bioorg. Med. Chem., 2012, 20(1), 69-85.
Sabbah, D.A.; Simms, N.A.; Wang, W.; Dong, Y.; Ezell, E.L.; Brattain, M.G.; Vennerstrom, J.L.; Zhong, H.A. N-Phenyl-4-hydroxy-2-quinolone-3-carboxamides as selective inhibitors of mutant H1047R phosphoinositide-3-kinase (PI3Kα). Bioorg. Med. Chem., 2012, 20(24), 7175-7183.
Sweidan, K.; Engelmann, J.; Abu Rayyan, W.; Sabbah, D.; Abu Zarga, M.; Al-Qirim, T.; Al-Hiari, Y.; Abu Sheikha, G.; Shattat, G. Synthesis and preliminary biological evaluation of new heterocyclic carboxamide models. Lett. Drug Des. Discov., 2015, 12(5), 417-429.
Sabbah, D.A.; Saada, M.; Khalaf, R.A.; Bardaweel, S.; Sweidan, K.; Al-Qirim, T.; Al-Zughier, A.; Halim, H.A.; Sheikha, G.A. Molecular modeling based approach, synthesis and cytotoxic activity of novel benzoin derivatives targeting phosphoinostide 3-kinase (PI3Kα). Bioorg. Med. Chem. Lett., 2015, 25(16), 3120-3124.
Sweidan, K.; Sabbah, D.A.; Bardaweel, S.; Dush, K.A.; Sheikha, G.A.; Mubarak, M.S. Computer-aided design, synthesis and biological evaluation of new indole-2-carboxamide derivatives as PI3Kα/EGFR inhibitors. Bioorg. Med. Chem. Lett., 2016, 26(11), 2685-2690.
Sweidan, K.; Sabbah, D.A.; Bardaweel, S.; Abu-Sheikha, G.; Al-Qirim, T.; Salih, H.; El-Abadelah, M.M.; Mubarak, M.S.; Voelter, W. Facile synthesis, characterization and cytotoxicity study of new 3-(indol-2-yl)bicyclotetrazatridecahexaens. Can. J. Chem., 2017, 95(8), 858-862.
Sabbah, D.A.; Hishmah, B.; Sweidan, K.; Bardaweel, S.; AlDamen, M.; Zhong, H.A.; Abu-Khalaf, R.; Ibrahim, A.H.; Al-Qirim, T.; Abu-Sheikha, G.; Mubarak, M.S. Structure-based design: Synthesis, x-ray crystallography and biological evaluation of n-substituted-4-hydroxy-2-quinolone-3-carboxamides as potential cytotoxic agents. Anticancer. Agents Med. Chem., 2018, 18, 263-276.
Kong, D.; Yamori, T. Advances in development of phosphatidylinositol 3-kinase inhibitors. Curr. Med. Chem., 2009, 16(22), 2839-2854.
Sabbah, D.A.; Brattain, M.G.; Zhong, H. Dual inhibitors of PI3K/mTOR or mTOR-selective inhibitors: Which way shall we go? Curr. Med. Chem., 2011, 18(36), 5528-5544.
Rodon, J.; Dienstmann, R.; Serra, V.; Tabernero, J. Development of PI3K inhibitors: Lessons learned from early clinical trials. Nat. Rev. Clin. Oncol., 2013, 10(3), 143-153.
Sabbah, D.A.; Hu, J.; Zhong, H.A. Advances in the development of class I phosphoinositide 3-kinase (PI3K). Curr. Top. Med. Chem., 2016, 16(13), 1413-1426.
Sabbah, D.A.; Simms, N.A.; Brattain, M.G.; Vennerstrom, J.L.; Zhong, H. Biological evaluation and docking studies of recently identified inhibitors of phosphoinositide-3-kinases. Bioorg. Med. Chem. Lett., 2012, 22(2), 876-880.
MOE. The Molecular Operating Environment; Chemical Computing Group, Inc Montreal: Quebec, Canada, 2016.
Sabbah, D.A.; Al-Tarawneh, F.; Talib, W.; Sweidan, K.; Bardaweel, S.; Al-Shalabi, E.; Zhong, H.A.; Sheikha, G.A.; Khalaf, R.A.; Mubarak, M.S. Benzoin schiff bases: Design, synthesis and biological evaluation as potential antitumor agents. Med. Chem., 2018, 14, 695-708.
Zhu, Y.; Wang, A.; Liu, M.C.; Zwart, A.; Lee, R.Y.; Gallagher, A.; Wang, Y.; Miller, W.R.; Dixon, J.M.; Clarke, R. Estrogen receptor alpha positive breast tumors and breast cancer cell lines share similarities in their transcriptome data structures. Int. J. Oncol., 2006, 29(6), 1581-1589.
Talib, W.H.; Mahasneh, A.M. Combination of Ononis hirta and Bifidobacterium longum decreases syngeneic mouse mammary tumor burden and enhances immune response. J. Cancer Res. Ther., 2012, 8(3), 417.
Talib, W.H. Consumption of garlic and lemon aqueous extracts combination reduces tumor burden by angiogenesis inhibition, apoptosis induction, and immune system modulation. Nutr. J., 2017, 43, 89-97.
Talib, W.H. Regressions of breast carcinoma syngraft following treatment with piperine in combination with thymoquinone. Sci. Pharm., 2017, 85(3), 27.
Raja, S.P.; Arunkumar, R.; Sivakamasundari, V.; Sharmila, G.; Elumalai, P.; Suganthapriya, E.; Brindha, M.A.; Senthil, K.K.; Arunakaran, J. Anti-proliferative and apoptosis inducing effect of nimbolide by altering molecules involved in apoptosis and IGF signalling via PI3K/Akt in prostate cancer (PC-3) cell line. Cell Biochem. Funct., 2014, 32(3), 217-228.
Du, J-Q.; Wu, J.; Zhang, H-J.; Zhang, Y-H.; Qiu, B-Y.; Wu, F.; Chen, Y-H.; Li, J-Y.; Nan, F-J.; Ding, J-P.; Li, J. Isoquinoline-1,3,4-trione derivatives inactivate caspase-3 by generation of reactive oxygen species. J. Biol. Chem., 2008, 283(44), 30205-30215.
Fanning, S.W.; Hodges-Gallagher, L.; Myles, D.C.; Sun, R.; Fowler, C.E.; Green, B.D.; Harmon, C.L.; Greene, G.L.; Kushner, P.J. Stereospecific methylpyrrolidine side chain of OP-1074 disrupts helix 12 of ESR1 and confers pure antiestrogenic activity. Nat. Commun., 2018, 9, Available at:.
Stender, J.D.; Nwachukwu, J.C.; Kastrati, I.; Kim, Y.; Strid, T.; Yakir, M.; Srinivasan, S.; Nowak, J.; Izard, T.; Rangarajan, E.S. Structural and molecular mechanisms of cytokine-mediated endocrine resistance in human breast cancer cells. Mol. Cell, 2017, 65(6), 1122-1135.
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.
Sabbah, D.A.; Hishmah, B.; Sweidan, K.; Bardaweel, S.; AlDamen, M.; Zhong, H.A.; Khalaf, R.A.; Hasan, I.A.; Al-Qirim, T.; Sheikha, G.A.; Mubarak, M.S. Structure-based design: synthesis, X-ray crystallography, and biological evaluation of N-substituted-4-hydroxy-2-quinolone-3-carboxamides as potential PI3Kα inhibitors. Anticancer. Agents Med. Chem., 2017. In Press
Schrödinger. Protein Preparation Wizard, Maestro, Macromodel, and QPLD-dock; 97204 2016.
Brattain, M.G.; Levine, A.E.; Chakrabarty, S.; Yeoman, L.C.; Willson, J.K.V.; Long, B. Heterogeneity of human colon carcinoma. Cancer Metastasis Rev., 1984, 3(3), 177-191.
Lauring, J.; Park, B.H.; Wolff, A.C. The phosphoinositide-3-kinase-Akt-mTOR pathway as a therapeutic target in breast cancer. J. Natl. Compr. Canc. Netw., 2013, 11(6), 670-678.
Wu, G.; Xing, M.; Mambo, E.; Huang, X.; Liu, J.; Guo, Z.; Chatterjee, A.; Goldenberg, D.; Gollin, S.M.; Sukumar, S.; Trink, B.; Sidransky, D. Somatic mutation and gain of copy number of PIK3CA in human breast cancer. Breast Cancer Res., 2005, 7(5), R609-R616.
Beaver, J.A.; Gustin, J.P.; Yi, K.H.; Rajpurohit, A.; Thomas, M.; Gilbert, S.F.; Rosen, D.M.; Park, B.H.; Lauring, J. PIK3CA and AKT1 mutations have distinct effects on sensitivity to targeted pathway inhibitors in an isogenic luminal breast cancer model system. Clin. Cancer Res., 2013, 19(19), 5413-5422.
She, Q-B.; Chandarlapaty, S.; Ye, Q.; Lobo, J.; Haskell, K.M.; Leander, K.R.; DeFeo-Jones, D.; Huber, H.E.; Rosen, N. Breast tumor cells with PI3K mutation or HER2 amplification are selectively addicted to Akt signaling. PLoS One, 2008, 3(8), e3065.
Weigelt, B.; Warne, P.H.; Downward, J. PIK3CA mutation, but not PTEN loss of function, determines the sensitivity of breast cancer cells to mTOR inhibitory drugs. Oncogene, 2011, 30(29), 3222-3233.
Zardavas, D.; Phillips, W.A.; Loi, S. PIK3CA mutations in breast cancer: Reconciling findings from preclinical and clinical data. Breast Cancer Res., 2014, 16(1), 201.
Ebi, H.; Costa, C.; Faber, A.C.; Nishtala, M.; Kotani, H.; Juric, D.; Della Pelle, P.; Song, Y.; Yano, S.; Mino-Kenudson, M.; Benes, C.H.; Engelman, J.A. PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1. Proc. Natl. Acad. Sci. USA, 2013, 110(52), 21124-21129.
Sanchez, C.G.; Ma, C.X.; Crowder, R.J.; Guintoli, T.; Phommaly, C.; Gao, F.; Lin, L.; Ellis, M.J. Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer. Breast Cancer Res., 2011, 13(2), R21.
Spangle, J.M.; Dreijerink, K.M.; Groner, A.C.; Cheng, H.; Ohlson, C.E.; Reyes, J.; Lin, C.Y.; Bradner, J.; Zhao, J.J.; Roberts, T.M.; Brown, M. PI3K/AKT Signaling regulates H3K4 methylation in breast cancer. Cell Rep, 2016, 15(12), 2692-2704.
Kataoka, Y.; Mukohara, T.; Shimada, H.; Saijo, N.; Hirai, M.; Minami, H. Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines. Ann. Oncol., 2010, 21(2), 255-262.
Sabine, V.S.; Crozier, C.; Brookes, C.L.; Drake, C.; Piper, T.; van de Velde, C.J.; Hasenburg, A.; Kieback, D.G.; Markopoulos, C.; Dirix, L. Mutational analysis of PI3K/AKT signaling pathway in tamoxifen exemestane adjuvant multinational pathology study. J. Clin. Oncol., 2014, 32(27), 2951-2958.
Liu, J-L.; Gao, G-R.; Zhang, X.; Cao, S-F.; Guo, C-L.; Wang, X.; Tong, L-J.; Ding, J.; Duan, W-H.; Meng, L-H. DW09849, a Selective phosphatidylinositol 3-Kinase (PI3K) inhibitor, prevents PI3K signaling and preferentially inhibits proliferation of cells containing the oncogenic mutation p110α (H1047R). J. Pharm. Exp. Ther., 2014, 348(3), 432-441.
Simi, L.; Pratesi, N.; Vignoli, M.; Sestini, R.; Cianchi, F.; Valanzano, R.; Nobili, S.; Mini, E.; Pazzagli, M.; Orlando, C. High-resolution melting analysis for rapid detection of KRAS, BRAF, and PIK3CA gene mutations in colorectal cancer. Am. J. Clin. Pathol., 2008, 130(2), 247-253.
Schneck, H.; Blassl, C.; Meier-Stiegen, F.; Neves, R.P.; Janni, W.; Fehm, T.; Neubauer, H. Analysing the mutational status of PIK3CA in circulating tumor cells from metastatic breast cancer patients. Mol. Oncol., 2013, 7(5), 976-986.
Rabi, T.; Huwiler, A.; Zangemeister-Wittke, U. AMR-Me inhibits PI3K/Akt signaling in hormone-dependent MCF-7 breast cancer cells and inactivates NF-κB in hormone-independent MDA-MB-231 cells. Mol. Carcinog., 2014, 53(7), 578-588.
Board, R.E.; Thelwell, N.J.; Ravetto, P.F.; Little, S.; Ranson, M.; Dive, C.; Hughes, A.; Whitcombe, D. Multiplexed assays for detection of mutations in PIK3CA. Clin. Chem., 2008, 54(4), 757-760.
Blair, B.G.; Wu, X.; Zahari, M.S.; Mohseni, M.; Cidado, J.; Wong, H.Y.; Beaver, J.A.; Cochran, R.L.; Zabransky, D.J.; Croessmann, S. A phosphoproteomic screen demonstrates differential dependence on HER3 for MAP kinase pathway activation by distinct PIK3CA mutations. Proteomics, 2015, 15(2-3), 318-326.
Song, J.; Yang, Q.; Lv, F.; Liu, L.; Wang, S. Visual detection of DNA mutation using multicolor fluorescent coding. ACS Appl. Mater. Interfaces, 2012, 4(6), 2885-2890.
Aksamitiene, E.; Kholodenko Bn Fau-Kolch, W.; Kolch, W. Fau-Hoek, J.B.; Hoek Jb Fau-Kiyatkin, A.; Kiyatkin, A. PI3K/Akt-sensitive MEK-independent compensatory circuit of ERK activation in ER-positive PI3K-mutant T47D breast cancer cells. Cell. Signal., 2010, 22(9), 1369-1378.
Li, G-Y.; Jung, K.H.; Lee, H.; Son, M.K.; Seo, J.; Hong, S-W.; Jeong, Y.; Hong, S.; Hong, S-S. A novel imidazopyridine derivative, HS-106, induces apoptosis of breast cancer cells and represses angiogenesis by targeting the PI3K/mTOR pathway. Cancer Lett., 2013, 329(1), 59-67.
Juric, D.; Castel, P.; Griffith, M.; Griffith, O.L.; Won, H.H.; Ellis, H.; Ebbesen, S.H.; Ainscough, B.J.; Ramu, A.; Iyer, G. Convergent loss of PTEN leads to clinical resistance to a PI (3) K α inhibitor. Nature, 2015, 518(7538), 240-244.
Bilbao, P.S.; Santillán, G.; Boland, R. ATP stimulates the proliferation of MCF-7 cells through the PI3K/Akt signaling pathway. Arch. Biochem. Biophys., 2010, 499(1-2), 40-48.
Park, S.K.; Hwang Ys Fau-Park, K-K.; Park Kk Fau-Park, H-J.; Park Hj Fau-Seo, J.Y.; Seo Jy Fau-Chung, W-Y.; Chung, W.Y. Kalopanaxsaponin A inhibits PMA-induced invasion by reducing matrix metalloproteinase-9 via PI3K/Akt- and PKCdelta-mediated signaling in MCF-7 human breast cancer cells. Carcinogenesis, 2009, 30, 1225-1233.
Mireuta, M.; Darnel, A.; Pollak, M. IGFBP-2 expression in MCF-7 cells is regulated by the PI3K/AKT/mTOR pathway through Sp1 induced increase in transcription. Growth Factors, 2010, 28(4), 243-255.
Ebi, H.; Costa, C.; Faber, A.C.; Nishtala, M.; Kotani, H.; Juric, D.; Della Pelle, P.; Song, Y.; Yano, S.; Mino-Kenudson, M.; Benes, C.H.; Engelman, J.A. PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1. Proc. Natl. Acad. Sci., 2013, 110(52), 21124-21129.
Baselga, J. Targeting the phosphoinositide-3 (PI3) kinase pathway in breast cancer. Oncologist, 2011, 16(S1), 12-19.
Friesner, R.A.; Banks, J.L.; Murphy, R.B.; Halgren, T.A.; Klicic, J.J.; Mainz, D.T.; Repasky, M.P.; Knoll, E.H.; Shelley, M.; Perry, J.K.; Shaw, D.E.; Francis, P.; Shenkin, P.S. Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem., 2004, 47(7), 1739-1749.
Friesner, R.A.; Murphy, R.B.; Repasky, M.P.; Frye, L.L.; Greenwood, J.R.; Halgren, T.A.; Sanschagrin, P.C.; Mainz, D.T. Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J. Med. Chem., 2006, 49(21), 6177-6196.
Sabbah, D.A.; Vennerstrom, J.L.; Zhong, H.A. Binding selectivity studies of phosphoinositide 3-kinases using free energy calculations. J. Chem. Inf. Model., 2012, 52, 3213-3224.
Sweidan, K.; Sabbah, D.A.; Engelmann, J.; Abdel-Halim, H.; Abu Sheikha, G. Computational docking studies of novel heterocyclic carboxamides as potential PI3Kα inhibitors. Lett. Drug Des. Discov., 2015, 12(10), 856-863.
Sabbah, D.A.; Sweidan, K. Molecular docking studies of novel thiosemicarbazone-based indoles as potential PI3Kalpha inhibitors. Lett. Drug Des. Discov., 2017, 14(11), 1252-1258.
Barsanti, P.A.; Aversa, R.J.; Jin, X.; Pan, Y.; Lu, Y.; Elling, R.; Jain, R.; Knapp, M.; Lan, J.; Lin, X.; Rudewicz, P.; Sim, J.; Taricani, L.; Thomas, G.; Xiao, L.; Yue, Q. Structure-based drug design of novel potent and selective tetrahydropyrazolo[1,5-a]pyrazines as ATR inhibitors. ACS Med. Chem. Lett., 2015, 6(1), 37-41.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [417 - 429]
Pages: 13
DOI: 10.2174/1573406414666180912111846
Price: $58

Article Metrics

PDF: 32
PRC: 1