Generic placeholder image

Mini-Reviews in Medicinal Chemistry


ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

Review Article

Anticancer Agents Based on Vulnerable Components in a Signalling Pathway

Author(s): Ankur Vaidya*, Shweta Jain, Sanjeev Sahu, Pankaj Kumar Jain, Kamla Pathak, Devender Pathak, Raj Kumar and Sanjay Kumar Jain

Volume 20, Issue 10, 2020

Page: [886 - 907] Pages: 22

DOI: 10.2174/1389557520666200212105417

Price: $65


Traditional cancer treatment includes surgery, chemotherapy, radiotherapy and immunotherapy that are clinically beneficial, but are associated with drawbacks such as drug resistance and side effects. In quest for better treatment, many new molecular targets have been introduced in the last few decades. Finding new molecular mechanisms encourages researchers to discover new anticancer agents. Exploring the mechanism of action also facilitates anticipation of potential resistance mechanisms and optimization of rational combination therapies. The write up describes the leading molecular mechanisms for cancer therapy, including mTOR, tyrosine Wee1 kinase (WEE1), Janus kinases, PI3K/mTOR signaling pathway, serine/threonine protein kinase AKT, checkpoint kinase 1 (Chk1), maternal embryonic leucine-zipper kinase (MELK), DNA methyltransferase I (DNMT1), poly (ADP-ribose) polymerase (PARP)-1/-2, sphingosine kinase-2 (SK2), pan-FGFR, inhibitor of apoptosis (IAP), murine double minute 2 (MDM2), Bcl-2 family protein and reactive oxygen species 1 (ROS1). Additionally, the manuscript reviews the anticancer drugs currently under clinical trials.

Keywords: Cancer, molecular mechanism, mTOR, WEE1, MELK, MDM2.

Graphical Abstract
Al-Lazikani, B.; Banerji, U.; Workman, P. Combinatorial drug therapy for cancer in the post-genomic era. Nat. Biotechnol., 2012, 30(7), 679-692.
[] [PMID: 22781697]
Zeng, Y. Advances in mechanism and treatment strategy of cancer. Cell. Mol. Biol., 2018, 64(6), 1-3.
[] [PMID: 29808792]
DeSantis, C.E.; Bray, F.; Ferlay, J.; Lortet-Tieulent, J.; Anderson, B.O.; Jemal, A. International variation in female breast cancer incidence and mortality rates. Cancer Epidemiol. Biomarkers Prev., 2015, 24(10), 1495-1506.
[] [PMID: 26359465]
Li, X.; Lewis, M.T.; Huang, J.; Gutierrez, C.; Osborne, C.K.; Wu, M.F.; Hilsenbeck, S.G.; Pavlick, A.; Zhang, X.; Chamness, G.C.; Wong, H.; Rosen, J.; Chang, J.C. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J. Natl. Cancer Inst., 2008, 100(9), 672-679.
[] [PMID: 18445819]
Shim, B.Y.; Park, S.H.; Lee, S.; Kim, J.S.; Lee, K.E.; Kang, Y.K.; Ahn, M.J. Current status and challenges of cancer clinical trials in Korea. Cancer Res. Treat., 2016, 48(1), 20-27.
[] [PMID: 25761486]
Grover, S.; Xu, M.; Jhingran, A.; Mahantshetty, U.; Chuang, L.; Small, W., Jr; Gaffney, D. Clinical trials in low and middle-income countries - Successes and challenges. Gynecol. Oncol. Rep., 2016, 19, 5-9.
[] [PMID: 28004030]
Laplante, M.; Sabatini, D.M. mTOR signaling in growth control and disease. Cell, 2012, 149(2), 274-293.
[] [PMID: 22500797]
Heitman, J.; Movva, N.R.; Hall, M.N. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science, 1991, 253(5022), 905-909.
[] [PMID: 1715094]
Nobes, C.D.; Hall, A. Rho GTPases control polarity, protrusion, and adhesion during cell movement. J. Cell Biol., 1999, 144(6), 1235-1244.
[] [PMID: 10087266]
Forbes, S.A.; Bindal, N.; Bamford, S.; Cole, C.; Kok, C.Y.; Beare, D.; Jia, M.; Shepherd, R.; Leung, K.; Menzies, A.; Teague, J.W.; Campbell, P.J.; Stratton, M.R.; Futreal, P.A. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res., 2011, 39(Database issue), D945-D950.
[] [PMID: 20952405]
Conciatori, F.; Ciuffreda, L.; Bazzichetto, C.; Falcone, I.; Pilotto, S.; Bria, E.; Cognetti, F.; Milella, M. mTOR Cross-Talk in Cancer and Potential for Combination Therapy. Cancers (Basel), 2018, 10(1), 1-30.
[] [PMID: 29351204]
Cheng, H.; Zou, Y.; Ross, J.S.; Wang, K.; Liu, X.; Halmos, B.; Ali, S.M.; Liu, H.; Verma, A.; Montagna, C.; Chachoua, A.; Goel, S.; Schwartz, E.L.; Zhu, C.; Shan, J.; Yu, Y.; Gritsman, K.; Yelensky, R.; Lipson, D.; Otto, G.; Hawryluk, M.; Stephens, P.J.; Miller, V.A.; Piperdi, B.; Perez-Soler, R. RICTOR amplification defines a novel subset of patients with lung cancer who may benefit from treatment with mTORC1/2 inhibitors. Cancer Discov., 2015, 5(12), 1262-1270.
[] [PMID: 26370156]
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.
[] [PMID: 19644473]
Benjamin, D.; Colombi, M.; Moroni, C.; Hall, M.N. Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat. Rev. Drug Discov., 2011, 10(11), 868-880.
[] [PMID: 22037041]
Gonzalez-Angulo, A.M.; Meric-Bernstam, F.; Chawla, S.; Falchook, G.; Hong, D.; Akcakanat, A.; Chen, H.; Naing, A.; Fu, S.; Wheler, J.; Moulder, S.; Helgason, T.; Li, S.; Elias, I.; Desai, N.; Kurzrock, R. Weekly nab-Rapamycin in patients with advanced nonhematologic malignancies: final results of a phase I trial. Clin. Cancer Res., 2013, 19(19), 5474-5484.
[] [PMID: 24089446]
Basu, B.; Dean, E.; Puglisi, M.; Greystoke, A.; Ong, M.; Burke, W.; Cavallin, M.; Bigley, G.; Womack, C.; Harrington, E.A.; Green, S.; Oelmann, E.; de Bono, J.S.; Ranson, M.; Banerji, U. First-in-human pharmacokinetic and pharmacodynamic study of the dual m-TORC 1/2 inhibitor; AZD2014. Clin. Cancer Res., 2015, 21(15), 3412-3419.
[] [PMID: 25805799]
Guichard, S.M.; Curwen, J.; Bihani, T.; D’Cruz, C.M.; Yates, J.W.; Grondine, M.; Howard, Z.; Davies, B.R.; Bigley, G.; Klinowska, T.; Pike, K.G.; Pass, M.; Chresta, C.M.; Polanska, U.M.; McEwen, R.; Delpuech, O.; Green, S.; Cosulich, S.C. AZD2014, an inhibitor of mTORC1 and mTORC2, is highly effective in ER+ breast cancer when administered using intermittent or continuous schedules. Mol. Cancer Ther., 2015, 14(11), 2508-2518.
[] [PMID: 26358751]
Smith, M.C.; Mader, M.M.; Cook, J.A.; Iversen, P.; Ajamie, R.; Perkins, E.; Bloem, L.; Yip, Y.Y.; Barda, D.A.; Waid, P.P.; Zeckner, D.J.; Young, D.A.; Sanchez-Felix, M.; Donoho, G.P.; Wacheck, V. Characterization of LY3023414; a novel PI3K/mTOR dual inhibitor eliciting transient target modulation to impede tumor growth. Mol. Cancer Ther., 2016, 15(10), 2344-2356.
[] [PMID: 27439478]
Bendell, J.C.; Varghese, A.M.; Hyman, D.M.; Bauer, T.M.; Pant, S.; Callies, S.; Lin, J.; Martinez, R.; Wickremsinhe, E.; Fink, A.; Wacheck, V.; Moore, K.N. A First-in-Human Phase 1 Study of LY3023414, an Oral PI3K/mTOR Dual Inhibitor, in Patients with Advanced Cancer. Clin. Cancer Res., 2018, 24(14), 3253-3262.
[] [PMID: 29636360]
Bellacosa, A.; Kumar, C.C.; Di Cristofano, A.; Testa, J.R. Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv. Cancer Res., 2005, 94, 29-86.
[] [PMID: 16095999]
Song, G.; Ouyang, G.; Bao, S. The activation of Akt/PKB signaling pathway and cell survival. J. Cell. Mol. Med., 2005, 9(1), 59-71.
[] [PMID: 15784165]
Altomare, D.A.; Khaled, A.R. Homeostasis and the importance for a balance between AKT/mTOR activity and intracellular signaling. Curr. Med. Chem., 2012, 19(22), 3748-3762.
[] [PMID: 22680924]
Levine, D.A.; Bogomolniy, F.; Yee, C.J.; Lash, A.; Barakat, R.R.; Borgen, P.I.; Boyd, J. Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin. Cancer Res., 2005, 11(8), 2875-2878.
[] [PMID: 15837735]
Mora, A.; Komander, D.; van Aalten, D.M.F.; Alessi, D.R. PDK1, the master regulator of AGC kinase signal transduction. Semin. Cell Dev. Biol., 2004, 15(2), 161-170.
[] [PMID: 15209375]
Nitulescu, G.M.; Margina, D.; Juzenas, P.; Peng, Q.; Olaru, O.T.; Saloustros, E.; Fenga, C.; Spandidos, D.Α.; Libra, M.; Tsatsakis, A.M. Akt inhibitors in cancer treatment: The long journey from drug discovery to clinical use (Review). Int. J. Oncol., 2016, 48(3), 869-885.
[] [PMID: 26698230]
Addie, M.; Ballard, P.; Buttar, D.; Crafter, C.; Currie, G.; Davies, B.R.; Debreczeni, J.; Dry, H.; Dudley, P.; Greenwood, R.; Johnson, P.D.; Kettle, J.G.; Lane, C.; Lamont, G.; Leach, A.; Luke, R.W.; Morris, J.; Ogilvie, D.; Page, K.; Pass, M.; Pearson, S.; Ruston, L. Discovery of 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an orally bioavailable, potent inhibitor of Akt kinases. J. Med. Chem., 2013, 56(5), 2059-2073.
[] [PMID: 23394218]
Li, J.; Davies, B.R.; Han, S.; Zhou, M.; Bai, Y.; Zhang, J.; Xu, Y.; Tang, L.; Wang, H.; Liu, Y.J.; Yin, X.; Ji, Q.; Yu, D.H. The AKT inhibitor AZD5363 is selectively active in PI3KCA mutant gastric cancer, and sensitizes a patient-derived gastric cancer xenograft model with PTEN loss to Taxotere. J. Transl. Med., 2013, 11, 241-250.
[] [PMID: 24088382]
Davies, B.R.; Greenwood, H.; Dudley, P.; Crafter, C.; Yu, D.H.; Zhang, J.; Li, J.; Gao, B.; Ji, Q.; Maynard, J. Preclinical pharmacology of AZD5363; an orally bioavailable inhibitor of AKT: Pharmacodynamics; antitumor activity and correlation of monotherapy activity with genetic background. Mol. Cancer Ther., 2012, 11, 873-887.
[] [PMID: 22294718]
Dean, E.; Banerji, U.; Schellens, J.H.M.; Krebs, M.G.; Jimenez, B.; van Brummelen, E.; Bailey, C.; Casson, E.; Cripps, D.; Cullberg, M.; Evans, S.; Foxley, A.; Lindemann, J.; Rugman, P.; Taylor, N.; Turner, G.; Yates, J.; Lawrence, P. A Phase 1, open-label, multicentre study to compare the capsule and tablet formulations of AZD5363 and explore the effect of food on the pharmacokinetic exposure, safety and tolerability of AZD5363 in patients with advanced solid malignancies: OAK. Cancer Chemother. Pharmacol., 2018, 81(5), 873-883.
[] [PMID: 29541803]
Faiman, B.; Richards, T. Innovative agents in multiple myeloma. J. Adv. Pract. Oncol., 2014, 5(3), 193-202.
[PMID: 25089218]
Burris, H.; Siu, L.; Infante, J.; Wheler, J.; Kurkjian, C.; Opalinska, J.; Smith, D.; Antal, J.; Gauvin, J.; Gonzalez, T. Safety; pharmacokinetics (PK); pharmacodynamics (PD); and clinical activity of the oral AKT inhibitor GSK2141795 (GSK795) in a phase I first-in-human study. J. Clin. Oncol., 2011, 194, 3003-3003.
Brown, J.S.; Banerji, U. Maximising the potential of AKT inhibitors as anti-cancer treatments. Pharmacol. Ther., 2017, 172, 101-115.
[] [PMID: 27919797]
Cheraghchi-Bashi, A.; Parker, C.A.; Curry, E.; Salazar, J.F.; Gungor, H.; Saleem, A.; Cunnea, P.; Rama, N.; Salinas, C.; Mills, G.B.; Morris, S.R.; Kumar, R.; Gabra, H.; Stronach, E.A. A putative biomarker signature for clinically effective AKT inhibition: correlation of in vitro, in vivo and clinical data identifies the importance of modulation of the mTORC1 pathway. Oncotarget, 2015, 6(39), 41736-41749.
[] [PMID: 26497682]
Dumble, M.; Crouthamel, M.C.; Zhang, S.Y.; Schaber, M.; Levy, D.; Robell, K.; Liu, Q.; Figueroa, D.J.; Minthorn, E.A.; Seefeld, M.A.; Rouse, M.B.; Rabindran, S.K.; Heerding, D.A.; Kumar, R. Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor. PLoS One, 2014, 9(6)e100880
[] [PMID: 24978597]
Wang, G.; Qiu, H.; Min, P.; Wu, M.; Dang, S.; Yang, C.; Zhang, F.; Zhuang, W.; Zhou, Z.; Fang, D.D. HQP1351; a novel multikinase inhibitor in clinical development; overcomes drug resistance for the treatment of gastrointestinal stromal tumors in preclinical models. Cancer Res., 2018, 78, 1-1.
Zhang, Y.; Hunter, T. Roles of Chk1 in cell biology and cancer therapy. Int. J. Cancer, 2014, 134(5), 1013-1023.
[] [PMID: 23613359]
O’Connell, M.J.; Raleigh, J.M.; Verkade, H.M.; Nurse, P. Chk1 is a wee1 kinase in the G2 DNA damage checkpoint inhibiting cdc2 by Y15 phosphorylation. EMBO J., 1997, 16(3), 545-554.
[] [PMID: 9034337]
Tang, J.; Erikson, R.L.; Liu, X. Checkpoint kinase 1 (Chk1) is required for mitotic progression through negative regulation of polo-like kinase 1 (Plk1). Proc. Natl. Acad. Sci. USA, 2006, 103(32), 11964-11969.
[] [PMID: 16873548]
King, C.; Diaz, H.B.; McNeely, S.; Barnard, D.; Dempsey, J.; Blosser, W.; Beckmann, R.; Barda, D.; Marshall, M.S. LY2606368 causes replication catastrophe and antitumor effects through CHK1-dependent mechanisms. Mol. Cancer Ther., 2015, 14(9), 2004-2013.
[] [PMID: 26141948]
Hong, D.; Infante, J.; Janku, F.; Jones, S.; Nguyen, L.M.; Burris, H.; Naing, A.; Bauer, T.M.; Piha-Paul, S.; Johnson, F.M.; Kurzrock, R.; Golden, L.; Hynes, S.; Lin, J.; Lin, A.B.; Bendell, J. Phase I study of LY2606368; a checkpoint kinase 1 inhibitor; in patients with advanced cancer. J. Clin. Oncol., 2016, 34(15), 1764-1771.
[] [PMID: 27044938]
Lowery, C.D.; VanWye, A.B.; Dowless, M.; Blosser, W.; Falcon, B.L.; Stewart, J.; Stephens, J.; Beckmann, R.P.; Bence Lin, A.; Stancato, L.F. The checkpoint kinase 1 inhibitor prexasertib induces regression of preclinical models of human neuroblastoma. Clin. Cancer Res., 2017, 23(15), 4354-4363.
[] [PMID: 28270495]
Lee, J.M.; Nair, J.; Zimmer, A.; Lipkowitz, S.; Annunziata, C.M.; Merino, M.J.; Swisher, E.M.; Harrell, M.I.; Trepel, J.B.; Lee, M.J.; Bagheri, M.H.; Botesteanu, D.A.; Steinberg, S.M.; Minasian, L.; Ekwede, I.; Kohn, E.C. Prexasertib, a cell cycle checkpoint kinase 1 and 2 inhibitor, in BRCA wild-type recurrent high-grade serous ovarian cancer: a first-in-class proof-of-concept phase 2 study. Lancet Oncol., 2018, 19(2), 207-215.
[] [PMID: 29361470]
Darnell, J.E., Jr; Kerr, I.M.; Stark, G.R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science, 1994, 264(5164), 1415-1421.
[] [PMID: 8197455]
Levy, D.E.; Darnell, J.E., Jr Stats: transcriptional control and biological impact. Nat. Rev. Mol. Cell Biol., 2002, 3(9), 651-662.
[] [PMID: 12209125]
Quintás-Cardama, A.; Kantarjian, H.; Cortes, J.; Verstovsek, S. Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Nat. Rev. Drug Discov., 2011, 10(2), 127-140.
[] [PMID: 21283107]
Migone, T.S.; Lin, J.X.; Cereseto, A.; Mulloy, J.C.; O’Shea, J.J.; Franchini, G.; Leonard, W.J. Constitutively activated Jak-STAT pathway in T cells transformed with HTLV-I. Science, 1995, 269(5220), 79-81.
[] [PMID: 7604283]
Kettle, J.G.; Su, Q.; Grimster, N.; Kawatkar, S.; Throner, S.; Woessner, R.; Chen, H.; Bebernitz, G.; Bell, K.; Anderson, E. Discovery of the JAK1 selective kinase inhibitor AZD4205; AACR. Cancer Res., 2017, •••, 77.
McGowan, C.H.; Russell, P. Cell cycle regulation of human WEE1. EMBO J., 1995, 14(10), 2166-2175.
[] [PMID: 7774574]
Murrow, L.M.; Garimella, S.V.; Jones, T.L.; Caplen, N.J.; Lipkowitz, S. Identification of WEE1 as a potential molecular target in cancer cells by RNAi screening of the human tyrosine kinome. Breast Cancer Res. Treat., 2010, 122(2), 347-357.
[] [PMID: 19821025]
Hirai, H.; Iwasawa, Y.; Okada, M.; Arai, T.; Nishibata, T.; Kobayashi, M.; Kimura, T.; Kaneko, N.; Ohtani, J.; Yamanaka, K.; Itadani, H.; Takahashi-Suzuki, I.; Fukasawa, K.; Oki, H.; Nambu, T.; Jiang, J.; Sakai, T.; Arakawa, H.; Sakamoto, T.; Sagara, T.; Yoshizumi, T.; Mizuarai, S.; Kotani, H. Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents. Mol. Cancer Ther., 2009, 8(11), 2992-3000.
[] [PMID: 19887545]
Rajeshkumar, N.V.; De Oliveira, E.; Ottenhof, N.; Watters, J.; Brooks, D.; Demuth, T.; Shumway, S.D.; Mizuarai, S.; Hirai, H.; Maitra, A.; Hidalgo, M. MK-1775, a potent Wee1 inhibitor, synergizes with gemcitabine to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts. Clin. Cancer Res., 2011, 17(9), 2799-2806.
[] [PMID: 21389100]
Do, K.; Wilsker, D.; Ji, J.; Zlott, J.; Freshwater, T.; Kinders, R.J.; Collins, J.; Chen, A.P.; Doroshow, J.H.; Kummar, S. Phase I study of single-agent AZD1775 (MK-1775). A wee1 kinase inhibitor; in patients with refractory solid tumors. J. Clin. Oncol., 2015, 33(30), 3409-3415.
[] [PMID: 25964244]
Zhang, M.; Dominguez, D.; Chen, S.; Fan, J.; Qin, L.; Long, A.; Li, X.; Zhang, Y.; Shi, H.; Zhang, B. WEE1 inhibition by MK1775 as a single-agent therapy inhibits ovarian cancer viability. Oncol. Lett., 2017, 14(3), 3580-3586.
[] [PMID: 28927115]
Tassan, J.P.; Le Goff, X. An overview of the KIN1/PAR-1/MARK kinase family. Biol. Cell, 2004, 96(3), 193-199.
[] [PMID: 15182702]
Lin, M.L.; Park, J.H.; Nishidate, T.; Nakamura, Y.; Katagiri, T. Involvement of maternal embryonic leucine zipper kinase (MELK) in mammary carcinogenesis through interaction with Bcl-G, a pro-apoptotic member of the Bcl-2 family. Breast Cancer Res., 2007, 9(1), R17.
[] [PMID: 17280616]
Alachkar, H.; Mutonga, M.B.; Metzeler, K.H.; Fulton, N.; Malnassy, G.; Herold, T.; Spiekermann, K.; Bohlander, S.K.; Hiddemann, W.; Matsuo, Y.; Stock, W.; Nakamura, Y. Preclinical efficacy of maternal embryonic leucine-zipper kinase (MELK) inhibition in acute myeloid leukemia. Oncotarget, 2014, 5(23), 12371-12382.
[] [PMID: 25365263]
Chung, S.; Suzuki, H.; Miyamoto, T.; Takamatsu, N.; Tatsuguchi, A.; Ueda, K.; Kijima, K.; Nakamura, Y.; Matsuo, Y. Development of an orally-administrative MELK-targeting inhibitor that suppresses the growth of various types of human cancer. Oncotarget, 2012, 3(12), 1629-1640.
[] [PMID: 23283305]
Chung, S.; Kijima, K.; Kudo, A.; Fujisawa, Y.; Harada, Y.; Taira, A.; Takamatsu, N.; Miyamoto, T.; Matsuo, Y.; Nakamura, Y. Preclinical evaluation of biomarkers associated with antitumor activity of MELK inhibitor. Oncotarget, 2016, 7(14), 18171-18182.
[] [PMID: 26918358]
Ji, W.; Arnst, C.; Tipton, A.R.; Bekier, M.E., II; Taylor, W.R.; Yen, T.J.; Liu, S.T. OTSSP167 abrogates mitotic checkpoint through inhibiting multiple mitotic kinases. PLoS One, 2016, 11(4)e0153518
[] [PMID: 27082996]
Jurmeister, S.; Ramos-Montoya, A.; Sandi, C.; Pértega-Gomes, N.; Wadhwa, K.; Lamb, A.D.; Dunning, M.J.; Attig, J.; Carroll, J.S.; Fryer, L.G.; Felisbino, S.L.; Neal, D.E. Identification of potential therapeutic targets in prostate cancer through a cross-species approach. EMBO Mol. Med., 2018, 10(3), 1-18.
[] [PMID: 29437778]
Okano, M.; Xie, S.; Li, E. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat. Genet., 1998, 19(3), 219-220.
[] [PMID: 9662389]
Santi, D.V.; Norment, A.; Garrett, C.E. Covalent bond formation between a DNA-cytosine methyltransferase and DNA containing 5-azacytosine. Proc. Natl. Acad. Sci. USA, 1984, 81(22), 6993-6997.
[] [PMID: 6209710]
Rountree, M.R.; Bachman, K.E.S.B.; Baylin, S.B. DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat. Genet., 2000, 25(3), 269-277.
[] [PMID: 10888872]
Detich, N.; Ramchandani, S.; Szyf, M. A conserved 3′-untranslated element mediates growth regulation of DNA methyltransferase 1 and inhibits its transforming activity. J. Biol. Chem., 2001, 276(27), 24881-24890.
[] [PMID: 11335728]
Parker, W.B.; Shaddix, S.C.; Rose, L.M.; Waud, W.R.; Shewach, D.S.; Tiwari, K.N.; Secrist, J.A., III Metabolism of 4′-thio-β-D-arabinofuranosylcytosine in CEM cells. Biochem. Pharmacol., 2000, 60(12), 1925-1932.
[] [PMID: 11108809]
Thottassery, J.V.; Tiwari, K.; Westbrook, L.; Secrist, J.A.; Parker, W.B. Novel 2′-deoxycytidine analogs as DNA demethylation agents. Proc. Am. Assoc. Cancer Res., 2011, 71, 291-302.
Thottassery, J.V.; Sambandam, V.; Allan, P.W.; Maddry, J.A.; Maxuitenko, Y.Y.; Tiwari, K.; Hollingshead, M.; Parker, W.B. Novel DNA methyltransferase-1 (DNMT1) depleting anticancer nucleosides, 4′-thio-2′-deoxycytidine and 5-aza-4′-thio-2′-deoxycytidine. Cancer Chemother. Pharmacol., 2014, 74(2), 291-302.
[] [PMID: 24908436]
Teicher, B.A.; Lock, R.B.; Collins, J.M.; Gorlick, R.; Kolb, E.A.; Houghton, P.J.; Kurmasheva, R.T.; Li, X.N.; Erickson, S.W.; Guo, Y. Pediatric Preclinical Testing Consortium evaluation of 4′-thio-2′-deoxycytidine (TdCyd) and 5-aza-4′-thio-2′-deoxycytidine (Aza-TdCyd). Int. Conf. Mol. Target Cancer Ther., 2018, pp. 26-30.
Amé, J.C.; Spenlehauer, C. Murcia, de. G. The PARP super-family. BioEssays, 2004, 2, 6882-6893.
D’Amours, D.; Desnoyers, S.; D’Silva, I.; Poirier, G.G. Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochem. J., 1999, 342(Pt 2), 249-268.
[] [PMID: 10455009]
Lee, M.; Park, J.T.; Lee, Y.S.; Moon, A.N.; Jeong, D.G.; Kim, J.A.; Yang, J.H.; Kim, D.; Shin, J.; Je, I.G. A comparative preclinical study of PARP inhibitors demonstrates superb properties for IDX-1197. Cancer Res., 2018, 78, 1-1.
Hannun, Y.A.; Obeid, L.M. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat. Rev. Mol. Cell Biol., 2008, 9(2), 139-150.
[] [PMID: 18216770]
Pitson, S.M. Regulation of sphingosine kinase and sphingolipid signaling. Trends Biochem. Sci., 2011, 36(2), 97-107.
[] [PMID: 20870412]
Liu, H.; Toman, R.E.; Goparaju, S.K.; Maceyka, M.; Nava, V.E.; Sankala, H.; Payne, S.G.; Bektas, M.; Ishii, I.; Chun, J.; Milstien, S.; Spiegel, S. Sphingosine kinase type 2 is a putative BH3-only protein that induces apoptosis. J. Biol. Chem., 2003, 278(41), 40330-40336.
[] [PMID: 12835323]
Miller, A.V.; Alvarez, S.E.; Spiegel, S.; Lebman, D.A. Sphingosine kinases and sphingosine-1-phosphate are critical for transforming growth factor beta-induced extracellular signal-regulated kinase 1 and 2 activation and promotion of migration and invasion of esophageal cancer cells. Mol. Cell. Biol., 2008, 28(12), 4142-4151.
[] [PMID: 18426913]
Hait, N.C.; Sarkar, S.; Le Stunff, H.; Mikami, A.; Maceyka, M.; Milstien, S.; Spiegel, S. Role of sphingosine kinase 2 in cell migration toward epidermal growth factor. J. Biol. Chem., 2005, 280(33), 29462-29469.
[] [PMID: 15951439]
French, K.J.; Zhuang, Y.; Maines, L.W.; Gao, P.; Wang, W.; Beljanski, V.; Upson, J.J.; Green, C.L.; Keller, S.N.; Smith, C.D. Pharmacology and antitumor activity of ABC294640, a selective inhibitor of sphingosine kinase-2. J. Pharmacol. Exp. Ther., 2010, 333(1), 129-139.
[] [PMID: 20061445]
Maines, L.W.; Fitzpatrick, L.R.; Green, C.L.; Zhuang, Y.; Smith, C.D. Efficacy of a novel sphingosine kinase inhibitor in experimental Crohn’s disease. Inflammopharmacology, 2010, 18(2), 73-85.
[] [PMID: 20151210]
Yang, J.; Yang, C.; Zhang, S.; Mei, Z.; Shi, M.; Sun, S.; Shi, L.; Wang, Z.; Wang, Y.; Li, Z.; Xie, C. ABC294640, a sphingosine kinase 2 inhibitor, enhances the antitumor effects of TRAIL in non-small cell lung cancer. Cancer Biol. Ther., 2015, 16(8), 1194-1204.
[] [PMID: 26054751]
Britten, C.D.; Garrett-Mayer, E.; Chin, S.H.; Shirai, K.; Ogretmen, B.; Bentz, T.A.; Brisendine, A.; Anderton, K.; Cusack, S.L.; Maines, L.W.; Zhuang, Y.; Smith, C.D.; Thomas, M.B. A Phase I Study of ABC294640, a First-in-Class sphingosine Kinase-2 inhibitor, in patients with advanced solid tumors. Clin. Cancer Res., 2017, 23(16), 4642-4650.
[] [PMID: 28420720]
Dieci, M.V.; Arnedos, M.; Andre, F.; Soria, J.C. Fibroblast growth factor receptor inhibitors as a cancer treatment: from a biologic rationale to medical perspectives. Cancer Discov., 2013, 3(3), 264-279.
[] [PMID: 23418312]
LaVallee, T.M.; Prudovsky, I.A.; McMahon, G.A.; Hu, X.; Maciag, T. Activation of the MAP kinase pathway by FGF-1 correlates with cell proliferation induction while activation of the Src pathway correlates with migration. J. Cell Biol., 1998, 141(7), 1647-1658.
[] [PMID: 9647656]
Hall, T.G.; Yu, Y.; Eathiraj, S.; Wang, Y.; Savage, R.E.; Lapierre, J.M.; Schwartz, B.; Abbadessa, G. Preclinical activity of ARQ 087; a novel inhibitor targeting FGFR dysregulation. PLoS One, 2016, 11(9)e0162594
[] [PMID: 27627808]
Papadopoulos, K.P.; El-Rayes, B.F.; Tolcher, A.W.; Patnaik, A.; Rasco, D.W.; Harvey, R.D.; LoRusso, P.M.; Sachdev, J.C.; Abbadessa, G.; Savage, R.E.; Hall, T.; Schwartz, B.; Wang, Y.; Kazakin, J.; Shaib, W.L. A Phase 1 study of ARQ 087, an oral pan-FGFR inhibitor in patients with advanced solid tumours. Br. J. Cancer, 2017, 117(11), 1592-1599.
[] [PMID: 28972963]
Chilà, R.; Hall G, T.; Abbadessa, G.; Broggini, M.; Damia, G. Multi-chemotherapeutic schedules containing the pan-FGFR inhibitor ARQ 087 are safe and show antitumor activity in different xenograft models. Transl. Oncol., 2017, 10(2), 153-157.
[] [PMID: 28161661]
Honda, R.; Yasuda, H. Association of p19(ARF) with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53. EMBO J., 1999, 18(1), 22-27.
[] [PMID: 9878046]
Gu, L.; Zhu, N.; Zhang, H.; Durden, D.L.; Feng, Y.; Zhou, M. Regulation of XIAP translation and induction by MDM2 following irradiation. Cancer Cell, 2009, 15(5), 363-375.
[] [PMID: 19411066]
Zhao, Y.; Yu, H.; Hu, W. The regulation of MDM2 oncogene and its impact on human cancers. Acta Biochim. Biophys. Sin. (Shanghai), 2014, 46(3), 180-189.
[] [PMID: 24389645]
Weisberg, E.; Halilovic, E.; Cooke, V.G.; Nonami, A.; Ren, T.; Sanda, T.; Simkin, I.; Yuan, J.; Antonakos, B.; Barys, L.; Ito, M.; Stone, R.; Galinsky, I.; Cowens, K.; Nelson, E.; Sattler, M.; Jeay, S.; Wuerthner, J.U.; McDonough, S.M.; Wiesmann, M.; Griffin, J.D. Inhibition of wild-type p53-expressing AML by novel small molecule HDM2 inhibitor; CGM097. Mol. Cancer Ther., 2015, 14(10), 2249-2259.
[] [PMID: 26206331]
Khoo, K.H.; Verma, C.S.; Lane, D.P. Drugging the p53 pathway: understanding the route to clinical efficacy. Nat. Rev. Drug Discov., 2014, 13(3), 217-236.
[] [PMID: 24577402]
Aguilar, A.; Lu, J.; Liu, L.; Du, D.; Bernard, D.; McEachern, D.; Przybranowski, S.; Li, X.; Luo, R.; Wen, B.; Sun, D.; Wang, H.; Wen, J.; Wang, G.; Zhai, Y.; Guo, M.; Yang, D.; Wang, S. Discovery of 4-((3‘R,4’S,5‘R)-6″-Chloro-4’-(3-chloro-2-fluorophenyl)-1′-ethyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)bicyclo[2.2.2]octane-1-carboxylic Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute 2 (MDM2) Inhibitor in Clinical Development. J. Med. Chem., 2017, 60(7), 2819-2839.
[] [PMID: 28339198]
Chen, H.; Luo, D.; Zhang, L.; Lin, X.; Luo, Q.; Yi, H.; Wang, J.; Yan, X.; Li, B.; Chen, Y.; Liu, X.; Zhang, H.; Liu, S.; Qiu, M.; Yang, D.; Jiang, N. Restoration of p53 using the novel MDM2-p53 antagonist APG115 suppresses dedifferentiated papillary thyroid cancer cells. Oncotarget, 2017, 8(26), 43008-43022.
[] [PMID: 28498808]
Yi, H.; Yan, X.; Luo, Q.; Yuan, L.; Li, B.; Pan, W.; Zhang, L.; Chen, H.; Wang, J.; Zhang, Y.; Zhai, Y.; Qiu, M.Z.; Yang, D.J. A novel small molecule inhibitor of MDM2-p53 (APG-115) enhances radiosensitivity of gastric adenocarcinoma. J. Exp. Clin. Cancer Res., 2018, 37(1), 97.
[] [PMID: 29716622]
LaCasse, E.C.; Mahoney, D.J.; Cheung, H.H.; Plenchette, S.; Baird, S.; Korneluk, R.G. IAP-targeted therapies for cancer. Oncogene, 2008, 27(48), 6252-6275.
[] [PMID: 18931692]
Lu, M.; Lin, S.C.; Huang, Y.; Kang, Y.J.; Rich, R.; Lo, Y.C.; Myszka, D.; Han, J.; Wu, H. XIAP induces NF-kappaB activation via the BIR1/TAB1 interaction and BIR1 dimerization. Mol. Cell, 2007, 26(5), 689-702.
[] [PMID: 17560374]
Varfolomeev, E.; Blankenship, J.W.; Wayson, S.M.; Fedorova, A.V.; Kayagaki, N.; Garg, P.; Zobel, K.; Dynek, J.N.; Elliott, L.O.; Wallweber, H.J.; Flygare, J.A.; Fairbrother, W.J.; Deshayes, K.; Dixit, V.M.; Vucic, D. IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell, 2007, 131(4), 669-681.
[] [PMID: 18022362]
Gao, Z.; Tian, Y.; Wang, J.; Yin, Q.; Wu, H.; Li, Y.M.; Jiang, X. A dimeric Smac/diablo peptide directly relieves caspase-3 inhibition by XIAP. Dynamic and cooperative regulation of XIAP by Smac/Diablo. J. Biol. Chem., 2007, 282(42), 30718-30727.
[] [PMID: 17724022]
Li, B.X.; Wang, H.B.; Qiu, M.Z.; Luo, Q.Y.; Yi, H.J.; Yan, X.L.; Pan, W.T.; Yuan, L.P.; Zhang, Y.X.; Xu, J.H.; Zhang, L.; Yang, D.J. Novel smac mimetic APG-1387 elicits ovarian cancer cell killing through TNF-alpha, Ripoptosome and autophagy mediated cell death pathway. J. Exp. Clin. Cancer Res., 2018, 37(1), 53-67.
[] [PMID: 29530056]
Pan, W.; Luo, Q.; Yan, X.; Yuan, L.; Yi, H.; Zhang, L.; Li, B.; Zhang, Y.; Sun, J.; Qiu, M.Z.; Yang, D.J. A novel SMAC mimetic APG-1387 exhibits dual antitumor effect on HBV-positive hepatocellular carcinoma with high expression of cIAP2 by inducing apoptosis and enhancing innate anti-tumor immunity. Biochem. Pharmacol., 2018, 154, 127-135.
[] [PMID: 29679556]
Adams, J.M.; Cory, S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene, 2007, 26(9), 1324-1337.
[] [PMID: 17322918]
O’Brien, S.M.; Cunningham, C.C.; Golenkov, A.K.; Turkina, A.G.; Novick, S.C.; Rai, K.R. Phase I to II multicenter study of oblimersen sodium, a Bcl-2 antisense oligonucleotide, in patients with advanced chronic lymphocytic leukemia. J. Clin. Oncol., 2005, 23(30), 7697-7702.
[] [PMID: 16186597]
Wang, J.; Yang, D.; Luo, Q.; Qiu, M.; Zhang, L.; Li, B.; Chen, H.; Yi, H.; Yan, X.; Li, S.; Sun, J. APG-1252-12A induces mitochondria-dependent apoptosis through inhibiting the antiapoptotic proteins Bcl-2/Bcl-xl in HL-60 cells. Int. J. Oncol., 2017, 51(2), 563-572.
[] [PMID: 28586007]
Storz, P. Reactive oxygen species in tumor progression. Front. Biosci., 2005, 10, 1881-1896.
[] [PMID: 15769673]
Chan, D.W.; Liu, V.W.; Tsao, G.S.; Yao, K.M.; Furukawa, T.; Chan, K.K.; Ngan, H.Y. Loss of MKP3 mediated by oxidative stress enhances tumorigenicity and chemoresistance of ovarian cancer cells. Carcinogenesis, 2008, 29(9), 1742-1750.
[] [PMID: 18632752]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy