Generic placeholder image

Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

General Review Article

Recent Advances in Multi-target Drugs Targeting Protein Kinases and Histone Deacetylases in Cancer Therapy

Author(s): Yong Ling*, Ji Liu, Jianqiang Qian, Chi Meng, Jing Guo, Weijie Gao, Biao Xiong, Changchun Ling and Yanan Zhang*

Volume 27 , Issue 42 , 2020

Page: [7264 - 7288] Pages: 25

DOI: 10.2174/0929867327666200102115720

Price: $65


Protein Kinase Inhibitors (PKIs) and Histone Deacetylase Inhibitors (HDACIs) are two important classes of anticancer agents and have provided a variety of small molecule drugs for the treatment of various types of human cancers. However, malignant tumors are of a multifactorial nature that can hardly be “cured” by targeting a single target, and treatment of cancers hence requires modulation of multiple biological targets to restore the physiological balance and generate sufficient therapeutic efficacy. Multi-target drugs have attracted great interest because of their advantages in the treatment of complex cancers by simultaneously targeting multiple signaling pathways and possibly leading to synergistic effects. Synergistic effects have been observed in the combination of kinase inhibitors, such as imatinib, dasatinib, or sorafenib, with an array of HDACIs including vorinostat, romidepsin, or panobinostat. A considerable number of multi-target agents based on PKIs and HDACIs have been developed. In this review, we summarize the recent literature on the development of multi-target kinase-HDAC inhibitors and provide our view on the challenges and future directions on this topic.

Keywords: Anticancer agents, multi-target, protein kinase inhibitor, histone deacetylase inhibitor, combination therapy, hybrids, receptor tyrosine kinases.

Csermely, P.; Agoston, V.; Pongor, S. The efficiency of multi-target drugs: the network approach might help drug design. Trends Pharmacol. Sci., 2005, 26(4), 178-182.
[] [PMID: 15808341]
Boran, A.D.; Iyengar, R. Systems approaches to polypharmacology and drug discovery. Curr. Opin. Drug Discov. Devel., 2010, 13(3), 297-309.
[PMID: 20443163]
Petrelli, A.; Giordano, S. From single- to multi-target drugs in cancer therapy: when aspecificity becomes an advantage. Curr. Med. Chem., 2008, 15(5), 422-432.
[] [PMID: 18288997]
Anighoro, A.; Bajorath, J.; Rastelli, G. Polypharmacology: challenges and opportunities in drug discovery. J. Med. Chem., 2014, 57(19), 7874-7887.
[] [PMID: 24946140]
Knight, Z.A.; Lin, H.; Shokat, K.M. Targeting the cancer kinome through polypharmacology. Nat. Rev. Cancer, 2010, 10(2), 130-137.
[] [PMID: 20094047]
Bayat Mokhtari, R.; Homayouni, T.S.; Baluch, N.; Morgatskaya, E.; Kumar, S.; Das, B.; Yeger, H. Combination therapy in combating cancer. Oncotarget, 2017, 8(23), 38022-38043.
[] [PMID: 28410237]
Gou, Y.; Zhang, Z.; Li, D.; Zhao, L.; Cai, M.; Sun, Z.; Li, Y.; Zhang, Y.; Khan, H.; Sun, H.; Wang, T.; Liang, H.; Yang, F. HSA-based multi-target combination therapy: regulating drugs’ release from HSA and overcoming single drug resistance in a breast cancer model. Drug Deliv., 2018, 25(1), 321-329.
[] [PMID: 29350051]
Zhou, L.; Shi, H.; Jiang, S.; Ruan, C.; Liu, H. Deep molecular response by IFN-α and dasatinib combination in a patient with T315I-mutated chronic myeloid leukemia. Pharmacogenomics, 2016, 17(10), 1159-1163.
[] [PMID: 27347777]
Xu, B.; Wang, Y.; Zhu, H. Mini-tablet combination for sustained release of clonidine hydrochloride and hydrochlorothiazide: Prepa-ration and pharmacokinetics in beagle dogs. Pharmazie, 2016, 71(2), 76-83.
[PMID: 27004371]
Guan, Z.; Xu, B.; DeSilvio, M.L.; Shen, Z.; Arpornwirat, W.; Tong, Z.; Lorvidhaya, V.; Jiang, Z.; Yang, J.; Makhson, A.; Leung, W.L.; Russo, M.W.; Newstat, B.; Wang, L.; Chen, G.; Oliva, C.; Gomez, H. Randomized trial of lapatinib versus placebo added to paclitaxel in the treatment of human epidermal growth factor receptor 2-overexpressing metastatic breast cancer. J. Clin. Oncol., 2013, 31(16), 1947-1953.
[] [PMID: 23509322]
Doycheva, I.; Thuluvath, P.J. Systemic therapy for advanced hepatocellular carcinoma: An update of a rapidly evolving field. J. Clin. Exp. Hepatol., 2019, 9(5), 588-596.
[] [PMID: 31695249]
Seo, Y.H. Dual inhibitors against topoisomerases and histone deacetylases. J. Cancer Prev., 2015, 20(2), 85-91.
[] [PMID: 26151040]
Ramsay, R.R.; Popovic-Nikolic, M.R.; Nikolic, K.; Uliassi, E.; Bolognesi, M.L. A perspective on multi-target drug discovery and design for complex diseases. Clin. Transl. Med., 2018, 7(1), 3.
[] [PMID: 29340951]
Higa, G.M.; Abraham, J. Lapatinib in the treatment of breast cancer. Expert Rev. Anticancer Ther., 2007, 7(9), 1183-1192.
[] [PMID: 17892419]
Manning, G.; Whyte, D.B.; Martinez, R.; Hunter, T.; Sudarsanam, S. The protein kinase complement of the human genome. Science, 2002, 298(5600), 1912-1934.
[] [PMID: 12471243]
Alonso, A.; Sasin, J.; Bottini, N.; Friedberg, I.; Friedberg, I.; Osterman, A.; Godzik, A.; Hunter, T.; Dixon, J.; Mustelin, T. Protein tyrosine phosphatases in the human genome. Cell, 2004, 117(6), 699-711.
[] [PMID: 15186772]
Liao, R.J.; Tong, L.J.; Huang, C.; Cao, W.W.; Wang, Y.Z.; Wang, J.; Chen, X.F.; Zhu, W.Z.; Zhang, W. Rescue of cardiac failing and remodelling by inhibition of protein phosphatase 1γ is associated with suppression of the alternative splicing factor-mediated splicing of Ca2+/calmodulin-dependent protein kinase δ. Clin. Exp. Pharmacol. Physiol., 2014, 41(12), 976-985.
[] [PMID: 25224648]
Maurer, G.; Tarkowski, B.; Baccarini, M. Raf kinases in cancer-roles and therapeutic opportunities. Oncogene, 2011, 30(32), 3477-3488.
[] [PMID: 21577205]
Fabbro, D.; Cowan-Jacob, S.W.; Moebitz, H. Ten things you should know about protein kinases: IUPHAR Review 14. Br. J. Pharmacol., 2015, 172(11), 2675-2700.
[] [PMID: 25630872]
Kittler, H.; Tschandl, P. Driver mutations in the mitogen-activated protein kinase pathway: the seeds of good and evil. Br. J. Dermatol., 2018, 178(1), 26-27.
[] [PMID: 29357585]
Fabian, M.A.; Biggs, W.H., III; Treiber, D.K.; Atteridge, C.E.; Azimioara, M.D.; Benedetti, M.G.; Carter, T.A.; Ciceri, P.; Edeen, P.T.; Floyd, M.; Ford, J.M.; Galvin, M.; Gerlach, J.L.; Grotzfeld, R.M.; Herrgard, S.; Insko, D.E.; Insko, M.A.; Lai, A.G.; Lélias, J.M.; Mehta, S.A.; Milanov, Z.V.; Velasco, A.M.; Wodicka, L.M.; Patel, H.K.; Zarrinkar, P.P.; Lockhart, D.J. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat. Biotechnol., 2005, 23(3), 329-336.
[] [PMID: 15711537]
Roskoski, R., Jr A historical overview of protein kinases and their targeted small molecule inhibitors. Pharmacol. Res., 2015, 100, 1-23.
[] [PMID: 26207888]
Kirkland, L.O.; McInnes, C. Non-ATP competitive protein kinase inhibitors as anti-tumor therapeutics. Biochem. Pharmacol., 2009, 77(10), 1561-1571.
[] [PMID: 19167366]
Wang, D.; Chang, R.; Wang, G.; Hu, B.; Qiang, Y.; Chen, Z. Polo-like kinase 1-targeting chitosan nanoparticles suppress the pro-gression of hepatocellular carcinoma. Anticancer. Agents Med. Chem., 2017, 17(7), 948-954.
[] [PMID: 27671301]
Kantarjian, H.M.; Fojo, T.; Mathisen, M.; Zwelling, L.A. Cancer drugs in the United States: justum pretium--the just price. J. Clin. Oncol., 2013, 31(28), 3600-3604.
[] [PMID: 23650428]
Roskoski, R., Jr The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacol. Res., 2014, 79, 34-74.
[] [PMID: 24269963]
Venugopal, B.; Evans, T.R.J. Developing histone deacetylase inhibitors as anti-cancer therapeutics. Curr. Med. Chem., 2011, 18(11), 1658-1671.
[] [PMID: 21428881]
Tsai, H.C.; Baylin, S.B. Cancer epigenetics: linking basic biology to clinical medicine. Cell Res., 2011, 21(3), 502-517.
[] [PMID: 21321605]
Füllgrabe, J.; Kavanagh, E.; Joseph, B. Histone onco-modifications. Oncogene, 2011, 30(31), 3391-3403.
[] [PMID: 21516126]
Bieler, A.; Mantwill, K.; Dravits, T.; Bernshausen, A.; Glockzin, G.; Köhler-Vargas, N.; Lage, H.; Gansbacher, B.; Holm, P.S. Novel three-pronged strategy to enhance cancer cell killing in glioblastoma cell lines: histone deacetylase inhibitor, chemotherapy, and on-colytic adenovirus dl520. Hum. Gene Ther., 2006, 17(1), 55-70.
[] [PMID: 16409125]
Sampson, E.R.; Amin, V.; Schwarz, E.M.; O’Keefe, R.J.; Rosier, R.N. The histone deacetylase inhibitor vorinostat selectively sensi-tizes fibrosarcoma cells to chemotherapy. J. Orthop. Res., 2011, 29(4), 623-632.
[] [PMID: 20957741]
Yang, C.; Choy, E.; Hornicek, F.J.; Wood, K.B.; Schwab, J.H.; Liu, X.; Mankin, H.; Duan, Z. Histone deacetylase inhibitor PCI-24781 enhances chemotherapy-induced apoptosis in multidrug-resistant sarcoma cell lines. Anticancer Res., 2011, 31(4), 1115-1123.
[PMID: 21508354]
Bode, A.M.; Dong, Z. Post-translational modification of p53 in tumorigenesis. Nat. Rev. Cancer, 2004, 4(10), 793-805.
[] [PMID: 15510160]
Chen, L.F.; Greene, W.C. Shaping the nuclear action of NF-kappaB. Nat. Rev. Mol. Cell Biol., 2004, 5(5), 392-401.
[] [PMID: 15122352]
Kovacs, J.J.; Murphy, P.J.; Gaillard, S.; Zhao, X.; Wu, J.T.; Nicchitta, C.V.; Yoshida, M.; Toft, D.O.; Pratt, W.B.; Yao, T.P. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol. Cell, 2005, 18(5), 601-607.
[] [PMID: 15916966]
Thiagalingam, S.; Cheng, K.H.; Lee, H.J.; Mineva, N.; Thiagalingam, A.; Ponte, J.F. Histone deacetylases: unique players in shaping the epigenetic histone code. Ann. N. Y. Acad. Sci., 2003, 983(1), 84-100.
[] [PMID: 12724214]
Marks, P.A.; Richon, V.M.; Rifkind, R.A. Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J. Natl. Cancer Inst., 2000, 92(15), 1210-1216.
[] [PMID: 10922406]
Liu, J.; Wang, T.; Wang, X.; Luo, L.; Guo, J.; Peng, Y.; Xu, Q.; Miao, J.; Zhang, Y.; Ling, Y. Development of novel β-carboline-based hydroxamate derivatives as HDAC inhibitors with DNA damage and apoptosis inducing abilities. MedChemComm, 2017, 8(6), 1213-1219.
[] [PMID: 30108831]
Zhao, X.; Tan, Q.; Zhang, Z.; Zhao, Y. 1,3,5-Triazine inhibitors of histone deacetylases: synthesis and biological activity. Med. Chem. Res., 2014, 23(12), 5188-5196.
Richon, V.M.; Emiliani, S.; Verdin, E.; Webb, Y.; Breslow, R.; Rifkind, R.A.; Marks, P.A. A class of hybrid polar inducers of trans-formed cell differentiation inhibits histone deacetylases. Proc. Natl. Acad. Sci. USA, 1998, 95(6), 3003-3007.
[] [PMID: 9501205]
Ueda, H.; Nakajima, H.; Hori, Y.; Fujita, T.; Nishimura, M.; Goto, T.; Okuhara, M. FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. I. Taxonomy, fermentation, isolation, physico-chemical and biological properties and antitumor activity. J. Antibiot. (Tokyo), 1994, 47(3), 301-310.
[] [PMID: 7513682]
Revill, P.; Mealy, N.; Serradell, N.; Bolos, J.; Rosa, E. Panobinostat. Drugs Future, 2007, 32(4), 315-322.
Thompson, C.A. Belinostat approved for use in treating rare lymphoma. Am. J. Health Syst. Pharm., 2014, 71(16), 1328.
[] [PMID: 25074945]
Gu, R.; Liu, T.; Zhu, X.; Gan, H.; Wu, Z.; Li, J.; Zheng, Y.; Dou, G.; Meng, Z. Development and validation of a sensitive HPLC-MS/MS method for determination of chidamide (epidaza), a new benzamide class of selective histone deacetylase inhibitor, in human plasma and its clinical application. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2015, 1000, 181-186.
[] [PMID: 26245362]
Vansteenkiste, J.; Van Cutsem, E.; Dumez, H.; Chen, C.; Ricker, J.L.; Randolph, S.S.; Schöffski, P. Early phase II trial of oral vori-nostat in relapsed or refractory breast, colorectal, or non-small cell lung cancer. Invest. New Drugs, 2008, 26(5), 483-488.
[] [PMID: 18425418]
Woyach, J.A.; Kloos, R.T.; Ringel, M.D.; Arbogast, D.; Collamore, M.; Zwiebel, J.A.; Grever, M.; Villalona-Calero, M.; Shah, M.H. Lack of therapeutic effect of the histone deacetylase inhibitor vorinostat in patients with metastatic radioiodine-refractory thyroid carcinoma. J. Clin. Endocrinol. Metab., 2009, 94(1), 164-170.
[] [PMID: 18854394]
Thurn, K.T.; Thomas, S.; Moore, A.; Munster, P.N. Rational therapeutic combinations with histone deacetylase inhibitors for the treatment of cancer. Future Oncol., 2011, 7(2), 263-283.
[] [PMID: 21345145]
Kalac, M.; Scotto, L.; Marchi, E.; Amengual, J.; Seshan, V.E.; Bhagat, G.; Ulahannan, N.; Leshchenko, V.V.; Temkin, A.M.; Parekh, S.; Tycko, B.; O’Connor, O.A. HDAC inhibitors and decitabine are highly synergistic and associated with unique gene-expression and epigenetic profiles in models of DLBCL. Blood, 2011, 118(20), 5506-5516.
[] [PMID: 21772049]
Seo, S.Y. Multi-targeted hybrids based on HDAC inhibitors for anti-cancer drug discovery. Arch. Pharm. Res., 2012, 35(2), 197-200.
[] [PMID: 22370774]
Kumar, S.; Singh, A.; Kumar, K.; Kumar, V. Recent insights into synthetic β-carbolines with anti-cancer activities. Eur. J. Med. Chem., 2017, 142, 48-73.
[] [PMID: 28583770]
Druker, B.J. Imatinib as a paradigm of targeted therapies. Adv. Cancer Res., 2004, 91, 1-30.
[] [PMID: 15327887]
Loren, C.P.; Aslan, J.E.; Rigg, R.A.; Nowak, M.S.; Healy, L.D.; Gruber, A.; Druker, B.J.; McCarty, O.J. The BCR-ABL inhibitor ponatinib inhibits platelet immunoreceptor tyrosine-based activation motif (ITAM) signaling, platelet activation and aggregate formation under shear. Thromb. Res., 2015, 135(1), 155-160.
[] [PMID: 25527332]
Shawver, L.K.; Lipson, K.E.; Fong, T.A.T.; McMahon, G.; Plowman, G.D.; Strawn, L.M. Receptor tyrosine kinases as targets for inhibition of angiogenesis. Drug Discov. Today, 1997, 2(2), 50-63.
Hanahan, D.; Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell, 1996, 86(3), 353-364.
[] [PMID: 8756718]
Sun, L.; Tran, N.; Liang, C.; Hubbard, S.; Tang, F.; Lipson, K.; Schreck, R.; Zhou, Y.; McMahon, G.; Tang, C. Identification of sub-stituted 3-[(4,5,6, 7-tetrahydro-1H-indol-2-yl)methylene]-1,3-dihydroindol-2-ones as growth factor receptor inhibitors for VEGF-R2 (Flk-1/KDR), FGF-R1, and PDGF-Rbeta tyrosine kinases. J. Med. Chem., 2000, 43(14), 2655-2663.
[] [PMID: 10893303]
Mahboobi, S.; Dove, S.; Sellmer, A.; Winkler, M.; Eichhorn, E.; Pongratz, H.; Ciossek, T.; Baer, T.; Maier, T.; Beckers, T. Design of chimeric histone deacetylase- and tyrosine kinase-inhibitors: a series of imatinib hybrides as potent inhibitors of wild-type and mutant BCR-ABL, PDGF-Rbeta, and histone deacetylases. J. Med. Chem., 2009, 52(8), 2265-2279.
[] [PMID: 19301902]
Hynes, N.E.; MacDonald, G. ErbB receptors and signaling pathways in cancer. Curr. Opin. Cell Biol., 2009, 21(2), 177-184.
[] [PMID: 19208461]
Jin, J.; Pawson, T. Modular evolution of phosphorylation-based signalling systems. Philos. Trans. R. Soc. Lond. B Biol. Sci., 2012, 367(1602), 2540-2555.
[] [PMID: 22889906]
Sirkisoon, S.R.; Carpenter, R.L.; Rimkus, T.; Miller, L.; Metheny-Barlow, L.; Lo, H.W. EGFR and HER2 signaling in breast cancer brain metastasis. Front. Biosci. (Elite Ed.), 2016, 8, 245-263.
[] [PMID: 26709660]
Ding, X.; Liu, X.; Song, X.; Yao, J. Chemotherapy drug response to the L858R-induced conformational change of EGFR activation loop in lung cancer. Mol. Inform., 2016, 35(10), 529-537.
[] [PMID: 27643705]
Mahboobi, S.; Sellmer, A.; Winkler, M.; Eichhorn, E.; Pongratz, H.; Ciossek, T.; Baer, T.; Maier, T.; Beckers, T. Novel chimeric histone deacetylase inhibitors: a series of lapatinib hybrides as potent inhibitors of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and histone deacetylase activity. J. Med. Chem., 2010, 53(24), 8546-8555.
[] [PMID: 21080629]
Cai, X.; Zhai, H.X.; Wang, J.; Forrester, J.; Qu, H.; Yin, L.; Lai, C.J.; Bao, R.; Qian, C. Discovery of 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDc-101) as a potent multi-acting HDAC, EGFR, and HER2 inhibitor for the treatment of cancer. J. Med. Chem., 2010, 53(5), 2000-2009.
[] [PMID: 20143778]
Lai, C.J.; Bao, R.; Tao, X.; Wang, J.; Atoyan, R.; Qu, H.; Wang, D.G.; Yin, L.; Samson, M.; Forrester, J.; Zifcak, B.; Xu, G.X.; Del-laRocca, S.; Zhai, H.X.; Cai, X.; Munger, W.E.; Keegan, M.; Pepicelli, C.V.; Qian, C. CUDC-101, a multitargeted inhibitor of histone deacetylase, epidermal growth factor receptor, and human epidermal growth factor receptor 2, exerts potent anticancer activity. Cancer Res., 2010, 70(9), 3647-3656.
[] [PMID: 20388807]
Wang, J.; Pursell, N.W.; Samson, M.E.; Atoyan, R.; Ma, A.W.; Selmi, A.; Xu, W.; Cai, X.; Voi, M.; Savagner, P.; Lai, C.J. Potential advantages of CUDC-101, a multitargeted HDAC, EGFR, and HER2 inhibitor, in treating drug resistance and preventing cancer cell migration and invasion. Mol. Cancer Ther., 2013, 12(6), 925-936.
[] [PMID: 23536719]
Ding, C.; Chen, S.; Zhang, C.; Hu, G.; Zhang, W.; Li, L.; Chen, Y.Z.; Tan, C.; Jiang, Y. Synthesis and investigation of novel 6-(1,2,3-triazol-4-yl)-4-aminoquinazolin derivatives possessing hydroxamic acid moiety for cancer therapy. Bioorg. Med. Chem., 2017, 25(1), 27-37.
[] [PMID: 27769671]
Haugsten, E.M.; Wiedlocha, A.; Olsnes, S.; Wesche, J. Roles of fibroblast growth factor receptors in carcinogenesis. Mol. Cancer Res., 2010, 8(11), 1439-1452.
[] [PMID: 21047773]
Turner, N.; Grose, R. Fibroblast growth factor signalling: from development to cancer. Nat. Rev. Cancer, 2010, 10(2), 116-129.
[] [PMID: 20094046]
Dienstmann, R.; Rodon, J.; Prat, A.; Perez-Garcia, J.; Adamo, B.; Felip, E.; Cortes, J.; Iafrate, A.J.; Nuciforo, P.; Tabernero, J. Ge-nomic aberrations in the FGFR pathway: opportunities for targeted therapies in solid tumors. Ann. Oncol., 2014, 25(3), 552-563.
[] [PMID: 24265351]
Knights, V.; Cook, S.J. De-regulated FGF receptors as therapeutic targets in cancer. Pharmacol. Ther., 2010, 125(1), 105-117.
[] [PMID: 19874848]
Liu, J.; Qian, C.; Zhu, Y.; Cai, J.; He, Y.; Li, J.; Wang, T.; Zhu, H.; Li, Z.; Li, W.; Hu, L. Design, synthesis and evaluate of novel dual FGFR1 and HDAC inhibitors bearing an indazole scaffold. Bioorg. Med. Chem., 2018, 26(3), 747-757.
[] [PMID: 29317150]
Sivendran, S.; Liu, Z.; Portas, L.J. Jr.; Yu, M.; Hahn, N.; Sonpavde, G.; Oh, W.K.; Galsky, M.D. Treatment-related mortality with vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy in patients with advanced solid tumors: a meta-analysis. Cancer Treat. Rev., 2012, 38(7), 919-925.
[] [PMID: 22651902]
Huang, J.; Mei, H.; Tang, Z.; Li, J.; Zhang, X.; Lu, Y.; Huang, F.; Jin, Q.; Wang, Z. Triple-amiRNA VEGFRs inhibition in pancreatic cancer improves the efficacy of chemotherapy through EMT regulation. J. Control. Release, 2017, 245, 1-14.
[] [PMID: 27889393]
Seto, T.; Higashiyama, M.; Funai, H.; Imamura, F.; Uematsu, K.; Seki, N.; Eguchi, K.; Yamanaka, T.; Ichinose, Y. Prognostic value of expression of vascular endothelial growth factor and its flt-1 and KDR receptors in stage I non-small-cell lung cancer. Lung Cancer, 2006, 53(1), 91-96.
[] [PMID: 16697074]
Terman, B.I.; Carrion, M.E.; Kovacs, E.; Rasmussen, B.A.; Eddy, R.L.; Shows, T.B. Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene, 1991, 6(9), 1677-1683.
[PMID: 1656371]
Fortin, S.; Bérubé, G. Advances in the development of hybrid anticancer drugs. Expert Opin. Drug Discov., 2013, 8(8), 1029-1047.
[] [PMID: 23646979]
Patel, H.; Chuckowree, I.; Coxhead, P.; Guille, M.; Wang, M.; Zuckermann, A.; Williams, R.S.B.; Librizzi, M.; Paranal, R.M.; Bradner, J.E.; Spencer, J. Synthesis of hybrid anticancer agents based on kinase and histone deacetylase inhibitors. MedChemComm, 2014, 5, 1829-1833.
Zang, J.; Liang, X.; Huang, Y.; Jia, Y.; Li, X.; Xu, W.; Chou, C.J.; Zhang, Y. Discovery of novel pazopanib-based HDAC and VEGFR dual inhibitors targeting cancer epigenetics and angiogenesis simultaneously. J. Med. Chem., 2018, 61(12), 5304-5322.
[] [PMID: 29787262]
Peng, F.W.; Xuan, J.; Wu, T.T.; Xue, J.Y.; Ren, Z.W.; Liu, D.K.; Wang, X.Q.; Chen, X.H.; Zhang, J.W.; Xu, Y.G.; Shi, L. Design, synthesis and biological evaluation of N-phenylquinazolin-4-amine hybrids as dual inhibitors of VEGFR-2 and HDAC. Eur. J. Med. Chem., 2016, 109, 1-12.
[] [PMID: 26741358]
Yamaoka, K.; Saharinen, P.; Pesu, M.; Holt, V.E., III; Silvennoinen, O.; O’Shea, J.J. Protein family review The Janus kinases (Jaks). Genome Biol., 2004, 5(12), 253.
[] [PMID: 15575979]
Zhao, L.; Wu, D.; Sang, M.; Xu, Y.; Liu, Z.; Wu, Q. Stachydrine ameliorates isoproterenol-induced cardiac hypertrophy and fibrosis by suppressing inflammation and oxidative stress through inhibiting NF-κB and JAK/STAT signaling pathways in rats. Int. Immunopharmacol., 2017, 48, 102-109.
[] [PMID: 28499193]
Zhu, Y.; Liu, Z.; Peng, Y.P.; Qiu, Y.H. Interleukin-10 inhibits neuroinflammation-mediated apoptosis of ventral mesencephalic neurons via JAK-STAT3 pathway. Int. Immunopharmacol., 2017, 50, 353-360.
[] [PMID: 28753520]
Ghoreschi, K.; Laurence, A.; O’Shea, J.J. Janus kinases in immune cell signaling. Immunol. Rev., 2009, 228(1), 273-287.
[] [PMID: 19290934]
Yang, E.G.; Mustafa, N.; Tan, E.C.; Poulsen, A.; Ramanujulu, P.M.; Chng, W.J.; Yen, J.J.; Dymock, B.W. Design and synthesis of januskinase 2 (JAK2) and histone deacetlyase (HDAC) bispecific inhibitors based on pacritinib and evidence of dual pathway inhibition in hematological cell lines. J. Med. Chem., 2016, 59(18), 8233-8262.
[] [PMID: 27541357]
Ning, C.Q.; Lu, C.; Hu, L.; Bi, Y.J.; Yao, L.; He, Y.J.; Liu, L.F.; Liu, X.Y.; Yu, N.F. Macrocyclic compounds as anti-cancer agents: design and synthesis of multi-acting inhibitors against HDAC, FLT3 and JAK2. Eur. J. Med. Chem., 2015, 95, 104-115.
[] [PMID: 25800646]
Yao, L.; Mustafa, N.; Tan, E.C.; Poulsen, A.; Singh, P.; Duong-Thi, M.D.; Lee, J.X.T.; Ramanujulu, P.M.; Chng, W.J.; Yen, J.J.Y.; Ohlson, S.; Dymock, B.W. Design and synthesis of ligand efficient dual inhibitors of janus kinase (JAK) and histone deacetylase (HDAC) based on ruxolitinib and vorinostat. J. Med. Chem., 2017, 60(20), 8336-8357.
[] [PMID: 28953386]
Yao, L.; Ramanujulu, P.M.; Poulsen, A.; Ohlson, S.; Dymock, B.W. Merging of ruxolitinib and vorinostat leads to highly potent inhibitors of JAK2 and histone deacetylase 6 (HDAC6). Bioorg. Med. Chem. Lett., 2018, 28(15), 2636-2640.
[] [PMID: 29945795]
Huang, Y.; Dong, G.; Li, H.; Liu, N.; Zhang, W.; Sheng, C. Discovery of janus kinase 2 (JAK2) and histone deacetylase (HDAC) dual inhibitors as a novel strategy for the combinational treatment of leukemia and invasive fungal infections. J. Med. Chem., 2018, 61(14), 6056-6074.
[] [PMID: 29940115]
Liang, X.; Zang, J.; Li, X.; Tang, S.; Huang, M.; Geng, M.; Chou, C.J.; Li, C.; Cao, Y.; Xu, W.; Liu, H.; Zhang, Y. Discovery of novel janus kinase (JAK) and histone deacetylase (HDAC) dual inhibitors for the treatment of hematological malignancies. J. Med. Chem., 2019, 62(8), 3898-3923.
[] [PMID: 30901208]
Thomas, S.M.; Brugge, J.S. Cellular functions regulated by Src family kinases. Annu. Rev. Cell Dev. Biol., 1997, 13, 513-609.
[] [PMID: 9442882]
Martin, G.S. The hunting of the Src. Nat. Rev. Mol. Cell Biol., 2001, 2(6), 467-475.
[] [PMID: 11389470]
Kostyniuk, C.L.; Dehm, S.M.; Batten, D.; Bonham, K. The ubiquitous and tissue specific promoters of the human SRC gene are repressed by inhibitors of histone deacetylases. Oncogene, 2002, 21(41), 6340-6347.
[] [PMID: 12214274]
Ko, K.S.; Steffey, M.E.; Brandvold, K.R.; Soellner, M.B. Development of a chimeric c-Src kinase and HDAC inhibitor. ACS Med. Chem. Lett., 2013, 4(8), 779-783.
[] [PMID: 24015327]
Brandvold, K.R.; Steffey, M.E.; Fox, C.C.; Soellner, M.B. Development of a highly selective c-Src kinase inhibitor. ACS Chem. Biol., 2012, 7(8), 1393-1398.
[] [PMID: 22594480]
Bahrami, A.; Shahidsales, S.; Khazaei, M.; Ghayour-Mobarhan, M.; Maftouh, M.; Hassanian, S.M.; Avan, A. C-Met as a potential target for the treatment of gastrointestinal cancer: Current status and future perspectives. J. Cell. Physiol., 2017, 232(10), 2657-2673.
[] [PMID: 28075018]
Avan, A.; Maftouh, M.; Funel, N.; Ghayour-Mobarhan, M.; Boggi, U.; Peters, G.J.; Giovannetti, E. MET as a potential target for the treatment of upper gastrointestinal cancers: characterization of novel c-Met inhibitors from bench to bedside. Curr. Med. Chem., 2014, 21(8), 975-989.
[] [PMID: 23992325]
Okuma, H.S.; Kondo, S. Trends in the development of MET inhibitors for hepatocellular carcinoma. Future Oncol., 2016, 12(10), 1275-1286.
[] [PMID: 26984595]
Jia, J.; Zhu, F.; Ma, X.; Cao, Z.; Cao, Z.W.; Li, Y.; Li, Y.X.; Chen, Y.Z. Mechanisms of drug combinations: interaction and network perspectives. Nat. Rev. Drug Discov., 2009, 8(2), 111-128.
[] [PMID: 19180105]
Matsumoto, Y.; Motoki, T.; Kubota, S.; Takigawa, M.; Tsubouchi, H.; Gohda, E. Inhibition of tumor-stromal interaction through HGF/Met signaling by valproic acid. Biochem. Biophys. Res. Commun., 2008, 366(1), 110-116.
[] [PMID: 18053801]
Lu, D.; Yan, J.; Wang, L.; Liu, H.; Zeng, L.; Zhang, M.; Duan, W.; Ji, Y.; Cao, J.; Geng, M.; Shen, A.; Hu, Y. Design, synthesis and biological evaluation of the first c-Met/HDAC inhibitors based on pyridazinone derivatives. ACS Med. Chem. Lett., 2017, 8(8), 830-834.
[] [PMID: 28835797]
Zhai, B.; Sun, X.Y. Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma. World J. Hepatol., 2013, 5(7), 345-352.
[] [PMID: 23898367]
Janku, F.; Kaseb, A.O.; Tsimberidou, A.M.; Wolff, R.A.; Kurzrock, R. Identification of novel therapeutic targets in the PI3K/AKT/mTOR pathway in hepatocellular carcinoma using targeted next generation sequencing. Oncotarget, 2014, 5(10), 3012-3022.
[] [PMID: 24931142]
Li, X.; Tao, J.; Cigliano, A.; Sini, M.; Calderaro, J.; Azoulay, D.; Wang, C.; Liu, Y.; Jiang, L.; Evert, K.; Demartis, M.I.; Ribback, S.; Utpatel, K.; Dombrowski, F.; Evert, M.; Calvisi, D.F.; Chen, X. Co-activation of PIK3CA and Yap promotes development of hepatocellular and cholangiocellular tumors in mouse and human liver. Oncotarget, 2015, 6(12), 10102-10115.
[] [PMID: 25826091]
Chen, K.F.; Chen, H.L.; Tai, W.T.; Feng, W.C.; Hsu, C.H.; Chen, P.J.; Cheng, A.L. Activation of phosphatidylinositol 3-kinase/Akt signaling pathway mediates acquired resistance to sorafenib in hepatocellular carcinoma cells. J. Pharmacol. Exp. Ther., 2011, 337(1), 155-161.
[] [PMID: 21205925]
Bendell, J.C.; Rodon, J.; Burris, H.A.; de Jonge, M.; Verweij, J.; Birle, D.; Demanse, D.; De Buck, S.S.; Ru, Q.C.; Peters, M.; Gold-brunner, M.; Baselga, J.; Phase, I. Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with ad-vanced solid tumors. J. Clin. Oncol., 2012, 30(3), 282-290.
[] [PMID: 22162589]
Sha, M.; Ye, J.; Zhang, L.X.; Luan, Z.Y.; Chen, Y.B.; Huang, J.X. Celastrol induces apoptosis of gastric cancer cells by miR-21 inhibiting PI3K/Akt-NF-κB signaling pathway. Pharmacology, 2014, 93(1-2), 39-46.
[] [PMID: 24434352]
Wang, F.; Ma, H.; Liu, Z.; Huang, W.; Xu, X.; Zhang, X. α-Mangostin inhibits DMBA/TPA-induced skin cancer through inhibiting inflammation and promoting autophagy and apoptosis by regulating PI3K/Akt/mTOR signaling pathway in mice. Biomed. Pharmacother., 2017, 92, 672-680.
[] [PMID: 28582759]
Aslam, A.; Coulson, I.H. Cowden syndrome (multiple hamartoma syndrome). Clin. Exp. Dermatol., 2013, 38(8), 957-959.
[] [PMID: 23905691]
Ler, S.Y.; Leung, C.H.; Khin, L.W.; Lu, G.D.; Salto-Tellez, M.; Hartman, M.; Iau, P.T.; Yap, C.T.; Hooi, S.C. HDAC1 and HDAC2 independently predict mortality in hepatocellular carcinoma by a competing risk regression model in a Southeast Asian population. Oncol. Rep., 2015, 34(5), 2238-2250.
[] [PMID: 26352599]
Wu, L.M.; Yang, Z.; Zhou, L.; Zhang, F.; Xie, H.Y.; Feng, X.W.; Wu, J.; Zheng, S.S. Identification of histone deacetylase 3 as a biomarker for tumor recurrence following liver transplantation in HBV-associated hepatocellular carcinoma. PLoS One, 2010, 5(12)e14460
[] [PMID: 21206745]
Rikimaru, T.; Taketomi, A.; Yamashita, Y.; Shirabe, K.; Hamatsu, T.; Shimada, M.; Maehara, Y. Clinical significance of histone deacetylase 1 expression in patients with hepatocellular carcinoma. Oncology, 2007, 72(1-2), 69-74.
[] [PMID: 18004079]
Qian, C.; Lai, C.J.; Bao, R.; Wang, D.G.; Wang, J.; Xu, G.X.; Atoyan, R.; Qu, H.; Yin, L.; Samson, M.; Zifcak, B.; Ma, A.W.; Del-laRocca, S.; Borek, M.; Zhai, H.X.; Cai, X.; Voi, M. Cancer network disruption by a single molecule inhibitor targeting both histone deacetylase activity and phosphatidylinositol 3-kinase signaling. Clin. Cancer Res., 2012, 18(15), 4104-4113.
[] [PMID: 22693356]
Chen, D.; Soh, C.K.; Goh, W.H.; Wang, H. Design, synthesis and preclinical evaluation offused pyrimidine-based hydroxamates for thetreatment of hepatocellular carcinoma. J. Med. Chem., 2018, 61(4), 1552-1575.
[] [PMID: 29360358]
Chen, Y.; Yuan, X.; Zhang, W.; Tang, M.; Zheng, L.; Wang, F.; Yan, W.; Yang, S.; Wei, Y.; He, J.; Chen, L. Discovery of novel dual histone deacetylase and mammalian target of rapamycin target inhibitors as a promising strategy for cancer therapy. J. Med. Chem., 2019, 62(3), 1577-1592.
[] [PMID: 30629434]
Asghar, U.; Witkiewicz, A.K.; Turner, N.C.; Knudsen, E.S. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat. Rev. Drug Discov., 2015, 14(2), 130-146.
[] [PMID: 25633797]
Graña, X.; Reddy, E.P. Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs). Oncogene, 1995, 11(2), 211-219.
[PMID: 7624138]
Malumbres, M.; Barbacid, M. To cycle or not to cycle: a critical decision in cancer. Nat. Rev. Cancer, 2001, 1(3), 222-231.
[] [PMID: 11902577]
Dickson, M.A. Molecular pathways: CDK4 inhibitors for cancer therapy. Clin. Cancer Res., 2014, 20(13), 3379-3383.
[] [PMID: 24795392]
O’Leary, B.; Finn, R.S.; Turner, N.C. Treating cancer with selective CDK4/6 inhibitors. Nat. Rev. Clin. Oncol., 2016, 13(7), 417-430.
[] [PMID: 27030077]
Hamilton, E.; Infante, J.R. Targeting CDK4/6 in patients with cancer. Cancer Treat. Rev., 2016, 45, 129-138.
[] [PMID: 27017286]
Huang, J.M.; Sheard, M.A.; Ji, L.; Sposto, R.; Keshelava, N. Combination of vorinostat and flavopiridol is selectively cytotoxic to multidrug-resistant neuroblastoma cell lines with mutant TP53. Mol. Cancer Ther., 2010, 9(12), 3289-3301.
[] [PMID: 21159612]
Li, Y.; Luo, X.; Guo, Q.; Nie, Y.; Wang, T.; Zhang, C.; Huang, Z.; Wang, X.; Liu, Y.; Chen, Y.; Zheng, J.; Yang, S.; Fan, Y.; Xiang, R. Discovery of N1-(4-((7-Cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]py-rimidin-2-yl)amino)phenyl)- N8-hydroxyoctanediamide as a novel inhibitor targeting cyclin-dependent kinase 4/9 (CDK4/9) and histone deacetlyase1 (HDAC1) against malignant cancer. J. Med. Chem., 2018, 61(7), 3166-3192.
[] [PMID: 29518312]
Huang, Z.; Zhou, W.; Li, Y.; Cao, M.; Wang, T.; Ma, Y.; Guo, Q.; Wang, X.; Zhang, C.; Zhang, C.; Shen, W.; Liu, Y.; Chen, Y.; Zheng, J.; Yang, S.; Fan, Y.; Xiang, R. Novel hybrid molecule overcomes the limited response of solid tumours to HDAC inhibitors via suppressing JAK1-STAT3-BCL2 signalling. Theranostics, 2018, 8(18), 4995-5011.
[] [PMID: 30429882]
Gysin, S.; Salt, M.; Young, A.; McCormick, F. Therapeutic strategies for targeting ras proteins. Genes Cancer, 2011, 2(3), 359-372.
[] [PMID: 21779505]
Eser, S.; Schnieke, A.; Schneider, G.; Saur, D. Oncogenic KRAS signalling in pancreatic cancer. Br. J. Cancer, 2014, 111(5), 817-822.
[] [PMID: 24755884]
Pylayeva-Gupta, Y.; Grabocka, E.; Bar-Sagi, D. RAS oncogenes: weaving a tumorigenic web. Nat. Rev. Cancer, 2011, 11(11), 761-774.
[] [PMID: 21993244]
Morelli, M.P.; Tentler, J.J.; Kulikowski, G.N.; Tan, A.C.; Bradshaw-Pierce, E.L.; Pitts, T.M.; Brown, A.M.; Nallapareddy, S.; Ar-caroli, J.J.; Serkova, N.J.; Hidalgo, M.; Ciardiello, F.; Eckhardt, S.G. Preclinical activity of the rational combination of selumetinib (AZD6244) in combination with vorinostat in KRAS-mutant colorectal cancer models. Clin. Cancer Res., 2012, 18(4), 1051-1062.
[] [PMID: 22173548]
Morotti, A.; Cilloni, D.; Messa, F.; Arruga, F.; Defilippi, I.; Carturan, S.; Catalano, R.; Rosso, V.; Chiarenza, A.; Pilatrino, C.; Guer-rasio, A.; Taulli, R.; Bracco, E.; Pautasso, M.; Baraban, D.; Gottardi, E.; Saglio, G. Valproate enhances imatinib-induced growth arrest and apoptosis in chronic myeloid leukemia cells. Cancer, 2006, 106(5), 1188-1196.
[] [PMID: 16444746]
Ling, Y.; Wang, X.; Wang, C.; Xu, C.; Zhang, W.; Zhang, Y.; Zhang, Y. Hybrids from farnesylthiosalicylic acid and hydroxamic acid as dual ras-related signaling and histone deacetylase (HDAC) inhibitors design, synthesis and biological evaluation. ChemMedChem, 2015, 10(6), 971-976.
[] [PMID: 25882299]
Morphy, R.; Rankovic, Z. Designed multiple ligands. An emerging drug discovery paradigm. J. Med. Chem., 2005, 48(21), 6523-6543.
[] [PMID: 16220969]
Muñoz-Torrero, D. Complexity against complexity: multitarget drugs. Curr. Med. Chem., 2013, 20(13), 1621-1622.
[] [PMID: 23458613]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy