Multi-Targeting Anticancer Agents: Rational Approaches, Synthetic Routes and Structure Activity Relationship

Author(s): Harbinder Singh, Nihar Kinarivala, Sahil Sharma*.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 19 , Issue 7 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


We live in a world with complex diseases such as cancer which cannot be cured with one-compound one-target based therapeutic paradigm. This could be due to the involvement of multiple pathogenic mechanisms. One-compound-various-targets stratagem has become a prevailing research topic in anti-cancer drug discovery. The simultaneous interruption of two or more targets has improved the therapeutic efficacy as compared to the specific targeted based therapy. In this review, six types of dual targeting agents along with some interesting strategies used for their design and synthesis are discussed. Their pharmacology with various types of the molecular interactions within their specific targets has also been described. This assemblage will reveal the recent trends and insights in front of the scientific community working in dual inhibitors and help them in designing the next generation of multi-targeted anti-cancer agents.

Keywords: Histone deacetylase, tubulin, topoisomerase, heat shock protein, kinase, anticancer.

Brown, D.; Superti, F.G. Rediscovering the sweet spot in drug discovery. Drug Discov. Today, 2003, 8, 1067-1077.
Overington, J.P.; Al-Lazikani, B.; Hopkins, A.L. How many drug targets are there? Nat. Rev. Drug Discov., 2006, 5, 993-996.
Szuromi, P.; Vinson, V.; Marshal, E. Rethinking drug discovery Science. Drug Discov. Today, 2004, 303, 1795.
Hartman, J.L.T.; Garvik, B.; Hartwell, L. Inciples for the buffering of genetic variation. Science, 2001, 291, 1001-1004.
[5] Assessed on 21-Jun-2018
Chen, S.; Chan, N.; Hsieh, T. New mechanistic and functional insights into DNA topoisomerases. Annu. Rev. Biochem., 2013, 82, 139-170.
Stringer, A.M.; Gibson, R.; Bowen, J.M.; Keefe, D. Chemotherapy-induced modifications to gastrointestinal microflora, evidence and implications of change. Curr. Drug Metab., 2009, 10, 79-83.
Stringer, A.; Gibson, R.; Logan, R.; Bowen, J.; Yeoh, A.; Laurence, J.; Keefe, D. Irinotecan-induced mucositis is associated with changes in intestinal mucins. Cancer Chemother. Pharmacol., 2009, 64, 123-132.
Lee, C.S.; Ryan, E.J.; Doherty, A.G. Gastro-intestinal toxicity of chemotherapeutics in colorectal cancer, the role of inflammation. World J. Gastroenterol., 2014, 20, 3751-3761.
Stein, A.; Voigt, W.; Jordan, K. Chemotherapy induced diarrhea, pathophysiology, frequency and guideline-based management. Ther. Adv. Med. Oncol., 2010, 2, 51-63.
Kwon, Y. Mechanism-based management for mucositis, option for treating side effects without compromising the efficacy of cancer therapy. OncoTargets Ther., 2016, 9, 2007-2016.
Fadeyi, O.O.; Adamson, S.T.; Myles, E.L.; Okoro, C.O. Novel fluorinated acridone derivatives, synthesis and evaluation as potential anticancer agents. Bioorg. Med. Chem. Lett., 2008, 18, 4172-4186.
Hidenori, N.; Young, B.K.; Hiroshi, T.; Minoru, Y.; Sueharu, H. FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor. Exp. Cell Res., 1998, 241, 126-133.
Ken, S.; Tadashi, K.; Hideki, S.; Akifumi, O.; Ohgi, T.; Chikashi, I. Romidepsin (FK228) and its analogs directly inhibit phosphatidylinositol 3-kinase activity and potently induce apoptosis as histone deacetylase/phosphatidylinositol 3-kinase dual inhibitors. Cancer Sci., 2012, 103, 1994-2001.
Odaa, A.B.C.; Ken, S.; Chikashi, I.; Koichi, N.; Tadashi, K.; Yurie, W.; Shuichi, F.; Ohgi, T. Predicting the structures of complexes between phosphoinositide3-kinase (PI3K) and romidepsin-related compounds for the drug design of PI3K/histone deacetylase dual inhibitors using computational docking and the ligand-based drug design approach. J. Mol. Graph. Model., 2014, 54, 46-53.
Ken, S.; Jin, I.; Koichi, N.; Akifumi, O.; Hideki, S.; Tadashi, K.; Chikashi, I. Biochemical, biological and structural properties of romidepsin (FK228) and its analogs as novel HDAC⁄PI3K dual inhibitors. Cancer Sci., 2015, 106, 208-215.
Ken, S.; Hiroo, I.; Sonoko, C.; Koichi, N.; Tadashi, K.; Chikashi, I. Antitumor activity and pharmacologic characterization of the depsipeptide analog as a novel histone deacetylase/ phosphatidylinositol 3-kinase dual inhibitor. Cancer Sci., 2017, 108, 1469-1475.
Stratikopoulos, E.E.; Dendy, M.; Szabolcs, M.; Khaykin, A.J.; Lefebvre, C.; Zhou, M.M.; Parsons, R. Kinase and BET inhibitors together clamp inhibition of PI3K signaling and overcome resistance to therapy. Cancer Cell, 2015, 27, 837-851.
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. Invest. New Drugs, 2013, 31, 734-741.
Mokhtari, R.B.; Homayouni, T.S.; Baluch, N.; Morgatskaya, E.; Kumar, S.; Das, B.; Yeger, H. Combination therapy in combating cancer. Oncotarget, 2017, 8, 38022-38043.
Mondello, P.; Derenzini, E.; Asgari, Z.; Philip, J.; Brea, E.J.; Seshan, V.; Hendrickson, R.C.; Stanchina, E.D.; Scheinberg, D.A.; Younes, A. Dual inhibition of histone deacetylases and phosphoinositide 3-kinase enhances therapeutic activity against B cell lymphoma. Oncotarget, 2017, 8, 14017-14028.
Andrews, F.H.; Singh, A.H.; Joshi, S.; Smith, C.A.; Morales, G.A.; Garlich, J.R.D.; Durden, D.L.; Kutateladze, T.G. Dual-activity PI3K-BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis. Proc. Natl. Acad. Sci. USA, 2017, 114, 1072-1080.
Mendel, D.B.; Laird, A.D.; Xin, X.; Louie, S.G.; Christensen, J.G.; Li, G.; Schreck, R.E.; Abrams, T.J.; Ngai, T.J.; Lee, L.B.; Murray, L.J.; Carver, J.; Chan, E.; Moss, K.G.J.; Haznedar, J.O.; Sukbuntherng, S.; Blake, R.A.; Sun, L.; Tang, C.; Miller, T.; Shirazian, S.; McMahon, G.; Cherrington, J.M. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors, determination of apharmacokinetic/pharmacodynamic relationship. Clin. Cancer Res., 2003, 9, 327-337.
Mitsui, H.; Takuwa, N.; Maruyama, T.; Maekawa, H.; Hirayama, H.; Sawatari, T.; Hashimoto, N.; Takuwa, Y.; Kimura, S. The MEK1-ERK map kinase pathway and the PI 3-kinase-Akt pathway independently mediate anti-apoptotic signals in HepG2 liver cancer cells. Int. J. Cancer, 2001, 92, 55-62.
Druker, B.J.; Lydon, N.B. Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J. Clin. Invest., 2000, 105, 3-7.
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.S.; DellaRocca, 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, 3647-3656.
Shimizu, T.; LoRusso, P.M.; Papadopoulos, K.P.; Patnaik, A.; Beeram, M.; Smith, L.S.; Rasco, D.W.; Mays, T.A.; Chambers, G.; Ma, A.; Wang, J.; Laliberte, R.; Voi, M.A.; Tolcher, A.W. Phase I first-inhuman study of CUDC-101, a multitargeted inhibitor of HDACs, EGFR, and HER2 in patients with advanced solid tumors. Clin. Cancer Res., 2014, 20, 5032-5040.
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, 925-936.
Seo, S.Y. Multi-targeted hybrids based on HDAC inhibitors for anti-cancer drug discovery. Arch. Pharm. Res., 2012, 35, 197-200.
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, 2000-2009.
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.; DellaRocca, 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, 4104-4113.
Kyu, Y.J.; Youngjoo, K. Proposal of dual inhibitor targeting ATPase domains of Topoisomerase II and heat shock protein 90. Biomol. Ther. , 2016, 24, 453-468.
Yingxiu, L.; Donghee, S.; So, H.K. Histone deacetylase 6 plays a role as a distinct regulator of diverse cellular processes. FEBS J., 2013, 280, 775-793.
Bertos, N.R.; Gilquin, B.; Chan, G.K.; Yen, T.J.; Khochbin, S.; Yang, X.J. Role of the tetradecapeptide repeat domain of human histone deacetylase 6 in cytoplasmic retention. J. Biol. Chem., 2014, 279, 48246-48254.
Ruijter, A.J.; Gennip, A.H.; Caron, H.N.; Kemp, S.; Kuilenburg, A.B.P. Histone deacetylases (HDACs) characterization of the classical HDAC family. Biochem. J., 2003, 370, 737-749.
Jeremy, M.J.K.; Longlong, W.; Makoto, S.; Daniel, H.; Xiaoning, W.; Bruce, J.M.; Paul, H.; Heinz, G.; Patrick, M. Structural insights into HDAC6 tubulin deacetylation and its selective inhibition. Nat. Chem. Biol., 2016, 12, 748-754.
Honore, S.; Pasquier, E.; Braguer, D. Understanding microtubule dynamics for improved cancer therapy. Cell. Mol. Life. Sci., 2005, 62, 3039-3056; b) Pellegrini, F.; Budman, D.R. Review: Tubulin function, action of antitubulin drugs, and new drug development. Cancer. Invest., 2005, 23, 264-273; c) Nepali, K.; Ojha, R.; Sharma, S.; Bedi, P.M.S.; Dhar, K.L. Tubulin inhibitors: A patent survey. Recent. Pat. Anti-Cancer Drug Discov., 2014, 9, 176-220.
Mehndiratta, S.; Sharma, S.; Kumar, S.; Nepali, K.; Rahman, A.; Zaman, K. Patents E Book Series; Bentham Science Publishers Ltd., 2015.
Xuan, Z.; Jie, Z.; Linjiang, T.; Yu, L.; Mingbo, S.; Yi, Z.; Jia, L.; Wei, L.; Yi, C. The discovery of colchicine-SAHA hybrids as a new class of antitumor Agents. Bioorg. Med. Chem., 2013, 21, 3240-3244.
Xuan, Z.; Yannan, K.; Jie, Z.; Mingbo, S.; Yubo, Z.; Yi, Z.; Jia, L.; Yi, C.; Yanfen, F.; Xiongwen, Z.; Wei, L. Design, synthesis and biological evaluation of colchicine derivatives as novel tubulin and histone deacetylase dual inhibitors. Eur. J. Med. Chem., 2015, 95, 127-135.
Hassanzadeh, M.; Bagherzadeh, K.; Amanlou, M. A comparative study based on docking and molecular dynamics simulations over HDAC-tubulin dual inhibitors. J. Mol. Graph. Model., 2016, 70, 170-180.
Zhang, X.; Zhang, J.; Su, M.; Zhou, Y.; Chen, Y.; Li, J.; Lu, W. Design, synthesis and biological evaluation of 4′-demethyl-4-deoxypodophyllotoxin derivatives as novel tubulin and histone deacetylase dual inhibitors. RSC Advances, 2014, 4, 40444-40448.
Liou, J.P.; Chang, Y.L.; Kuo, F.M.; Chang, C.W.; Tseng, H.Y.; Wang, C.C.; Yang, Y.N.; Chang, J.Y.; Lee, S.J.; Hsieh, H.P. Concise synthesis and structure-activity relationships of combretastatin A-4 analogues, 1-aroylindoles and 3-aroylindoles, as novel classes of potent antitubulin agents. J. Med. Chem., 2004, 47, 4247-4257.
Kuo, C.C.; Hsieh, H.P.; Pan, W.Y.; Chen, C.P.; Liou, J.P.; Lee, S.J.; Chang, Y.L.; Chen, L.T.; Chen, C.T.; Chang, J.Y. BPR0L075, a novel synthetic indole compound with antimitotic activity in human cancer cells, exerts effective antitumoral activity in vivo. Cancer Res., 2004, 64, 4621-4628.
Hsueh, Y.L.; Jiann, F.L.; Sunil, K.; Yi, W.W.; Wei, C.F.; Mei, J.L.; Yu, H.L.; Hsiang, L.H.; Fei, C.K.; Che, J.H.; Chun, C.C.; Chia, R.Y.; Jing, P.L. 3-Aroylindoles display antitumor activity in vitro and in vivo: Effects of N1-substituents on biological activity. Eur. J. Med. Chem., 2017, 125, 1268-1278.
Wei, C.H.; Min, W.C.; Chun, C.C.; Yu, C.W.; Yi, W.W.; Jing, P.L.; George, H.; Yu, C.L.; Chia, R.Y. Anti-leukemia effects of the novel synthetic 1-benzylindole derivative 21-900 in vitro and in vivo. Sci. Rep., 2017, 7, 42291-42303.
Seigneuric, R.; Mjahed, H.; Gobbo, J.; Joly, A.; Berthenet, K.; Shirley, S.; Garrido, C. Heat shock proteins as danger signals for cancer detection. Front. Oncol., 2011, 1, 1-10.
Kampinga, H.H.; Hageman, J.; Vos, M.J.; Kubota, H.; Tanguay, R.M.; Bruford, E.A.; Cheetham, M.E.; Chen, B.; Hightower, L.E. Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones, 2009, 14, 105-111.
Joly, A.L.; Wettstein, G.; Mignot, G.; Ghiringhelli, F.; Garrido, C. Dual role of heat shock proteins as regulators of apoptosis and innate immunity. J. Innate Immun., 2010, 2, 238-247.
Calderwood, S.K.; Khaleque, M.A.; Sawyer, D.B.; Ciocca, D.R. Heat shock proteins in cancer: Chaperones of tumorigenesis. Trends Biochem. Sci., 2006, 31, 164-172.
Neckers, L.; Workman, P. Hsp90 molecular chaper-one inhibitors: Are we there yet? Clin. Cancer Res., 2012, 18, 64-76.
Meng, L.; Hunt, C.; Yaglom, J.A.; Gabai, V.L.; Sherman, M.Y. Heat shock protein Hsp72 plays an essential role in Her2-induced mammary tumorigenesis. Oncogene, 2011, 30, 2836-2845.
Kuo, C.C.; Hsieh, H.P.; Pan, W.Y.; Chen, C.P.; Liou, J.P.; Lee, S.J.; Chang, Y.L.; Chen, L.T.; Chen, C.T.; Chang, J.Y. BPR0L075, a novel synthetic indole compound with antimitotic activity in human cancer cells, exerts effective antitumoral activity in vivo. Cancer Res., 2004, 64, 4621-4628.
Andrew, J.S.K.; Trevor, P.; Michal, P.; Georgia, G.; Christopher, T.F.; Darren, F.; Williams, D.C.; Meegan, M.J.; Lloyd, D.G. Integration of ligand and structure-based virtual screening for the identification of the first dual targeting agent for Heat Shock Protein 90 (Hsp90) and tubulin. J. Med. Chem., 2009, 52, 2177-2180.
Baoping, Y.; Guoyong, H.; Jieping, Y.; Zongxue, R.; Hesheng, L. Cyclooxygenase-2 inhibitor nimesulide suppresses telomerase activity by blocking Akt/PKB activation in gastric cancer cell line. Dig. Dis. Sci., 2004, 49, 948-953.
Elder, D.J.; Halton, D.E.; Hague, A.; Paraskeva, C. Induction of apoptotic cell death in human colorectal carcinoma cell lines by a cyclooxygenase-2 (COX-2)-selective nonsteroidal anti-inflammatory drug: Independence from COX-2 protein expression. Clin. Cancer Res., 1997, 3, 1679-1683.
Hanif, R.; Pittas, A.; Feng, Y.; Koutsos, M.I.; Qiao, L.; Staiano-Coico, L.; Shiff, S.I.; Rigas, B. Effects of nonsteroidal anti-inflammatory drugs on proliferation and on induction of apoptosis in colon cancer cells by a prostaglandin-independent pathway. Biochem. Pharmacol., 1996, 52, 237-245.
Johnson, A.J.; Song, X.; Hsu, A.; Chen, C. Apoptosis signaling pathways mediated by cyclooxygenase-2 inhibitors in prostate cancer cells. Adv. Enzyme Regul., 2001, 41, 221-235.
Pan, Y.; Zhang, J.S.; Gazi, M.H.; Young, C.Y. The cyclooxygenase 2-specific nonsteroidal anti-inflammatory drugs celecoxib and nimesulide inhibit androgen receptor activity via induction of c-Jun in prostate cancer cells. Cancer Epidemiol. Biomarkers Prev., 2003, 12, 769-774.
Shiff, S.J.; Koutsos, M.I.; Qiao, L.; Rigas, B. Nonsteroidal antiinflammatory drugs inhibit the proliferation of colon adenocarcinoma cells: Effects on cell cycle and apoptosis. Exp. Cell Res., 1996, 222, 179-188.
Zhong, B.; Cai, X.; Chennamaneni, S.; Yi, X.; Liu, L.; Pink, J.J.; Dowlati, A.; Xu, Y.; Zhou, A.; Su, B. From COX-2 inhibitor nimesulide to potent anti-cancer agent: synthesis, in vitro, in vivo and pharmacokinetic evaluation. Eur. J. Med. Chem., 2012, 47, 432-444.
Yi, X.; Zhong, B.; Smith, K.M.; Geldenhuys, W.J.; Feng, Y.; Pink, J.J.A.; Dowlati, A.; Xu, Y.; Zhou, A.; Su, B. Identification of a class of novel tubulin inhibitors. J. Med. Chem., 2012, 55, 3425-3435.
Zhong, B.; Chennamaneni, S.; Lama, R.; Yi, X.; Geldenhuys, W.J.; Pink, J.J.; Dowlati, A.; Xu, Y.; Zhou, A.; Su, B. Synthesis and anticancer mechanism investigation of dual Hsp27 and tubulin inhibitors. J. Med. Chem., 2013, 56, 5306-5320.
Zhong, B.; Lama, R.; Kulman, D.G.; Li, B.; Su, B. Lead optimization of dual tubulin and Hsp27 inhibitors. Eur. J. Med. Chem., 2014, 80, 243-253.
Zhou, H.Y.; Wu, S.H.; Zhai, S.M.; Liu, A.F.; Sun, Y.; Li, R.S.; Zhang, Y.; Ekins, S.; Swaan, P.W.; Fang, B.; Zhang, B.; Yan, B. Design, synthesis, cytoselective toxicity, structure-activity relationships, and pharmacophore of thiazolidinone derivatives targeting drug-resistant lung cancer cells. J. Med. Chem., 2008, 51, 1242-1251.
Zhang, Q.; Zhai, S.; Li, L.; Li, X.; Zhou, H.; Liu, A.; Su, G.; Mu, Q.; Du, Y.; Yan, B. Anti-tumor selectivity of a novel Tubulin and HSP90 dual-targeting inhibitor in non-small cell lung cancer models. Biochem. Pharmacol., 2013, 86, 351-360.
Hargreaves, R.H.; David, C.L.; Whitesell, L.J.; Labarbera, D.V.; Jamil, A.; Chapuis, J.C.; Skibo, E.B. Discovery of quinolinediones exhibiting a heat shock response and angiogenesis inhibition. J. Med. Chem., 2008, 51, 2492-2501.
Nien, C.Y.; Chen, Y.C.; Kuo, C.C.; Hsieh, H.P.; Chang, C.Y.; Wu, J.S.; Wu, S.Y.; Liou, J.P.; Chang, J.Y. 5-Amino-2-aroylquinolines as highly potent tubulin polymerization inhibitors. J. Med. Chem., 2010, 53, 2309-2313.
Nepali, K.; Kumar, S.; Huang, H.L.; Kuo, F.C.; Lee, C.H.; Kuo, C.C.; Yeh, T.K.; Li, Y.H.; Chang, J.Y.; Liou, J.P.; Lee, H.Y. 2-Aroylquinoline-5,8-diones as potent anticancer agents displaying tubulin and heat shock protein 90 (HSP90) inhibition. Org. Biomol. Chem., 2016, 14, 716-723.
Sengupta, S.K.; Foye, W.O. Inhibitors of DNA topoisomerases. In: Cancer Chemotherapeutic Agents; American Chemical Society: DC, 1995; pp. 205-217.
Wang, J.C. Cellular roles of DNA topoisomerases: A molecular perspective. Nat. Rev. Mol. Cell Biol., 2002, 3, 430-440.
Pommier, Y.; Leo, E.; Zhang, H.; Marchand, C. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem. Biol., 2010, 17, 421-433.
Chen, S.H.; Chan, N.L.; Hsieh, T.S. New mechanistic and functional insights into DNA topoisomerases. Annu. Rev. Biochem., 2013, 82, 139-170.
Champoux, J.J. DNA topoisomerases: Structure, function, and mechanism. Annu. Rev. Biochem., 2001, 70, 369-413.
Nitiss, J.L. DNA topoisomerase II and its growing repertoire of biological functions. Nat. Rev. Cancer, 2009, 9, 327-337.
Vos, S.M.; Tretter, E.M.; Schmidt, B.H.; Berger, J.M. All tangled up: how cells direct, manage and exploit topoisomerase function. Nat. Rev. Mol. Cell Biol., 2011, 12, 827-841.
Ashour, M.E.; Atteya, R.; Khamisy, S.F.E. Topoisomerase-mediated chromosomal break repair: An emerging player in many games. Nat. Rev. Cancer, 2015, 15, 137-151.
Chang, J.Y.; Hsieh, H.P.; Pan, W.Y.; Liou, J.P.; Bey, S.J.; Chena, L.T.; Liu, J.F.; Song, J.S. Dual inhibition of topoisomerase I and tubulin polymerization by BPR0Y007, a novel cytotoxic agent. Biochem. Pharmacol., 2003, 65, 2009-2019.
Leon, L.G.; Luci, C.R.; Tejedor, D.; Roth, E.P.; Montero, J.C.; Pandiella, A.; Tellado, F.G.; Padron, J.M. Mitotic arrest induced by a novel family of DNA Topoisomerase II inhibitors. J. Med. Chem., 2010, 53, 3835-3839.
Renic, A.P.; Bankovic, J.; Dinic, J.; Luci, C.R.; Miguel, X.F.; Ortega, N.; Grujicic, N.K.; Victor, S.M.; Jose, M.P.; Pesic, M. DTA0100, dual topoisomerase II and microtubule inhibitor, evades paclitaxel resistance in P-glycoprotein overexpressing cancer cells. Eur. J. Pharm. Sci., 2017, 15, 159-168.
Diana, P.; Martorana, A.; Barraja, P.; Montalbano, A.; Dattolo, G.; Cirrincione, G.; Francesco, D.A.; Salvador, A.; Vedaldi, D.; Basso, G.; Viola, G. Isoindolo[2,1-a]quinoxaline derivatives, novel potent antitumor agents with dual inhibition of tubulin polymerization and topoisomerase I. J. Med. Chem., 2008, 51, 2387-2399.
Chiou, W.F.; Sung, Y.J.; Liao, J.F.; Shum, A.Y.; Chen, C.F. Inhibitory effect of dehydroevodiamine and evodiamine on nitric oxide production in cultured murine macrophages. J. Nat. Prod., 1997, 60, 708-711.
Ko, H.C.; Wang, Y.H.; Liou, K.T.; Chen, C.M.; Chen, C.H.; Wang, W.Y.; Chang, S.; Hou, Y.C.; Chen, K.T.; Chen, C.F.; Shen, Y.C. Anti-inflammatory effects and mechanisms of the ethanol extract of Evodia rutaecarpa and its bioactive components on neutrophils and microglial cells. Eur. J. Pharmacol., 2007, 555, 211-217.
Kobayashi, Y.; Nakano, Y.; Kizaki, M.; Hoshikuma, K.; Yokoo, Y.; Kamiya, T. Capsaicin-like anti-obese activities of evodiamine from fruits of Evodia rutaecarpa, a vanilloid receptor agonist. Planta Med., 2001, 67, 628-633.
Jiang, J.; Hu, C. Evodiamine: A novel anti-cancer alkaloid from Evodia rutaecarpa. Molecules, 2009, 14, 1852-1859.
Shengzheng, W.; Kun, F.; Guoqiang, D.; Shuqiang, C.; Na, L.; Zhenyuan, M.; Jianzhong, Y.; Jian, L.; Zhang, W.; Sheng, C. Scaffold diversity inspired by the natural product evodiamine: Discovery of highly potent and multitargeting antitumor agents. J. Med. Chem., 2015, 58, 6678-6696.
Guerrant, W.; Patil, V.; Canzoneri, J.C.; Oyelere, A.K. Dual targeting of histone deacetylase and topoisomerase II with novel bifunctional inhibitors. J. Med. Chem., 2012, 55, 1465-1477.
Zhang, R.; Li, Y.; Cai, Q.; Liu, T.H.; Sun, B. Chambless, Preclinical pharmacology of the natural products anticancer agents 10-hydroxyxamptothecin, an inhibitor of topoisomerase I. Cancer Chemother. Pharmacol., 1998, 41, 257-267.
Chen, Z.S.; Furukawa, T.; Sumizawa, T.; Ono, K.; Ueda, K.; Seto, K.; Akiyama, S.I. ATP-dependent efflux of CPT-11 and SN-38 by the Multidrug Resistance Protein (MRP) and its inhibition by PAK-104P. Mol. Pharmacol., 1999, 55, 921-928.
Sugimori, M.; Ejima, A.; Ohsuki, S.; Uoto, K.; Mitsui, I.; Matsumoto, K.; Kawato, Y.; Yasuoka, M.; Sato, M.; Tagawa, H.; Terasawa, H. Synthesis and antitumor activity of novel hexacyclic camptothecin analogues. J. Med. Chem., 1994, 37, 3033-3039.
Leu, Y.L.; Chen, C.S.; Wu, Y.J.; Chern, J.W. Benzyl ether-linked glucuronide derivative of 10-hydroxycamptothecin designed for selective camptothecin-based anticancer therapy. J. Med. Chem., 2008, 51, 1740; (b) Ulukan, H.; Swaan, P.W. Camptothecins: A review of their chemotherapeutic potential. Drugs, 2002, 6, 2039-2057.
Guerrant, W.; Patil, V.; Canzoneri, J.C.; Yao, L.P.; Hood, R.; Oyelere, A.K. Dual-acting histone deacetylase-topoisomerase I inhibitors. Bioorg. Med. Chem. Lett., 2013, 23, 3283-3287.
Zhang, X.; Bao, B.; Yu, X.; Tong, L.; Luo, Y.; Huang, Q.; Su, M.; Sheng, L.; Li, J.; Zhu, H.; Yang, B.; Zhang, X.; Chen, Y.; Lu, W. The discovery and optimization of novel dual inhibitors of topoisomerase II and histone deacetylase. Bioorg. Med. Chem., 2013, 21, 6981-6995.
Yu, C.C.; Pan, S.L.; Chao, S.W.; Liu, S.P.; Hsu, J.L.; Yang, Y.C.; Li, T.K.; Huang, W.J.; Guh, J.H. A novel small molecule hybrid of vorinostat and DACA displays anticancer activity against human hormone-refractory metastatic prostate cancer through dual inhibition of histone deacetylase and topoisomerase I. Biochem. Pharmacol., 2014, 90, 320-330.
He, S.; Dong, G.; Wang, Z.; Chen, W.; Huang, Y.; Li, Z.; Jiang, Y.; Liu, N.; Yao, J.; Miao, Z.; Zhang, W.; Sheng, C. Discovery of novel multiacting topoisomerase I/II and histone deacetylase inhibitors. ACS Med. Chem. Lett., 2015, 6, 239-243.
Manning, G.; Whyte, D.B.; Martinez, R.; Hunter, T.; Sudarsanam, S. The protein kinase complement of the human genome. Science, 2002, 298, 1912-1934.
Stehelin, D.; Varmus, H.E.; Bishop, J.M.; Vogt, P.K. DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature, 1976, 260, 170-173.
Hunter, T.; Cooper, J.A. Protein-tyrosine kinases. Annu. Rev. Biochem., 1985, 54, 897-930.
Krishnegowda, G.; Gowda, A.S.P.; Tagaram, H.R.S.; Carroll, O.K.F.; Irby, R.B.; Sharma, A.K.; Amin, S. Synthesis and biological evaluation of a novel class of isatin analogs as dual inhibitors of tubulin polymerization and Akt pathway. Bioorg. Med. Chem., 2011, 19, 6006-6014.
Guo, L.; Liu, X.; Nishikawa, K.; Plunkett, W. Inhibition of topoisomerase II alpha and G2 cell cycle arrest by NK314, a novel benzo[c]phenanthridine currently in clinical trials. Mol. Cancer Ther., 2007, 6, 1501-1508.
Onda, T.; Toyoda, E.; Miyazaki, O.; Seno, C.; Kagaya, S.; Okamoto, K.; Nishhikawa, K. NK314, a novel topoisomerase II inhibitor, induces rapid DNA double-strand breaks and exhibits superior antitumor effects against tumors resistant to other topoisomerase II inhibitors. Cancer Lett., 2008, 259, 99-110.
Toyoda, E.; Kagaya, S.; Cowell, I.G.; Kurosawa, A.; Kamoshita, K.; Nishikawa, K.; Iiizumi, S.; Koyama, H.; Austin, C.A.; Adachi, N. NK314, a topoisomerase II inhibitor that specifically targets the alpha isoform. J. Biol. Chem., 2008, 283, 23711-23720.
Takashi, H.; Naoko, S.A.; Akemi, S.; Rika, T.; Masaru, I.; Akihiro, K.; Kazuya, O.; Shinya, K.; Eisaburo, S. NK314 potentiates antitumor activity with adult T-cell leukemia-lymphoma cells by inhibition of dual targets on topoisomerase IIα and DNA-dependent protein kinase. Blood, 2011, 117, 3575-3584.
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.S.; Rocca, S.D.; 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, 4104-4113.
Nakanishi, T.; Shiozawa, K.; Hassel, B.A.; Ross, D.D. Complex interaction of BCRP/ABCG2 and imatinib in BCR-ABL-expressing cells: BCRP-mediated resistance to imatinib is attenuated by imatinib induced reduction of BCRP expression. Blood, 2006, 108, 678-684.
Hegedus, C.; Ozvegy Laczka, C.; Apati, A.; Magocsi, M.; Nemet, K.; Orfi, L.; Keri, G.; Katona, M.; Takats, Z.; Varadi, A.; Szakacs, G.; Sarkadi, B. Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: Implications for altered anti-cancer effects and pharmacological properties. Br. J. Pharmacol., 2009, 158, 1153-1164.
Burger, H.; Tol, H.V.; Brok, M.; Wiemer, E.A.; Bruijn, E.A.; Guetens, G.; Boeck, G.; Sparreboom, A.; Verweij, J.; Nooter, K. Chronic imatinib mesylate exposure leads to reduced intracellular drug accumulation by induction of the ABCG2 (BCRP) and ABCB1 (MDR1) drug transport pumps. Cancer Biol. Ther., 2005, 4, 747-752.
Mahon, F.X.; Belloc, F.; Lagarde, V.; Chollet, C.; Gaudry, F.M.; Reiffers, J.; Goldman, J.M.; Melo, J.V. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood, 2003, 101, 2368-2373.
Thomas, J.; Wang, L.; Clark, R.E.; Pirmohamed, M. Active transport of imatinib into and out of cells: implications for drug resistance. Blood, 2004, 104, 3739-3745.
Wu, C.P.; Hsieh, Y.J.; Hsia, S.H.; Su, C.Y.; Li, Y.Q.; Huang, Y.H.; Huang, C.W.; Hsieh, C.H.; Yu, J.S.; Wu, Y.S. Human ATP-binding cassette transporter ABCG2 confers resistance to CUDC-907, a dual inhibitor of histone deacetylase and phosphatidylinositol 3-kinase. Mol. Pharm., 2016, 13, 784-794.
Younes, A.; Berdeja, J.G.; Patel, M.R.; Flinn, I.; Gerecitano, J.F.; Neelapu, S.S.; Kelly, K.R.; Copeland, A.R.; Akins, A.; Clancy, M.S.; Gong, L.; Wang, J.; Ma, A.; Viner, J.L.; Oki, Y. Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: An open-label, dose-escalation, phase 1 trial. Lancet Oncol., 2016, 17, 622-631.
Zhang, X.; Su, M.; Chen, Y.; Li, J.; Lu, W. The design and synthesis of a new class of RTK/HDAC dual-targeted inhibitors. Molecules, 2013, 18, 6491-6503.
Zhao, Y.; Su, J.; Goto, M.; Natschke, S.L.M.; Li, Y.; Zhao, Q.S.; Yao, Z.J.; Lee, K.H. Dual-functional abeo-taxane derivatives destabilizing microtubule equilibrium and inhibiting NF-κB activation. J. Med. Chem., 2013, 56, 4749-4757.
Zhou, H.Y.; Wu, S.H.; Zhai, S.M.; Liu, A.F.; Sun, Y.; Li, R.S.; Zhang, Y.; Ekins, S.; Swaan, P.W.; Fang, B.L.; Zhang, B.; Yan, B. Design, synthesis, cytoselective toxicity, structure-activity relationships, and pharmacophore of thiazolidinone derivatives targeting drug-resistant lung cancer cells. J. Med. Chem., 2008, 51, 1242-1251.
Li, L.; Zhang, Q.; Liu, A.; Li, X.; Zhou, H.; Liu, Y.; Yan, B. Proteome interrogation using nanoprobes to identify targets of a cancer-killing molecule. J. Am. Chem. Soc., 2011, 133, 6886-6889.
Zhang, Q.; Zhai, S.; Li, L.; Li, X.; Zhou, H.; Liu, A.; Su, G.; Mu, Q.; Du, Y.; Yan, B. Anti-tumor selectivity of a novel Tubulin and HSP90 dual-targeting inhibitor in non-small cell lung cancer models. Biochem. Pharmacol., 2013, 86, 351-360.
Li, L.; Liu, Y.; Zhang, Q.; Zhou, H.; Zhang, Y.; Yan, B. Comparison of cancer cell survival triggered by microtubule damage after turning Dyrk1B kinase on and off. ACS Chem. Biol., 2014, 9, 731-742.
Zhang, X.; Raghavan, S.; Ihnat, M.; Thorpe, J.E.; Disch, B.C.; Bastian, A.; Downs, L.C.; Hargreaves, N.F.D.; Rohena, C.C.; Hamel, E.; Mooberry, S.L.; Gangjee, A. The design and discovery of water soluble 4-substituted-2, 6-dimethylfuro[2,3-d]pyrimidines as multitargeted receptor tyrosine kinase inhibitors and microtubule targeting antitumor agents. Bioorg. Med. Chem., 2014, 22, 3753-3772.
Peng, T.; Wu, J.R.; Tong, L.J.; Li, M.Y.; Chen, F.; Leng, Y.X.; Qu, R.; Han, K.; Su, Y.; Chen, Y.; Duan, W.H.; Xie, H.; Ding, J. Identification of DW532 as a novel anti-tumor agent targeting both kinases and tubulin. Acta Pharmacol. Sin., 2014, 35, 916-928.
Niino, M.K.; Tokmakoz, A.; Terada, T.; Ohbayashi, N.; Fujimoto, T.; Gomi, S.; Shiromizu, I.; Kawamoto, M.; Matsusue, T.; Shirouzu, M.; Yokoyama, S. Inhibitor-bound structures of human pyruvate dehydrogenase kinase 4. Biol. Crystallogr., 2011, 67, 763-773.
Meng, T.; Zhang, D.; Xie, Z.; Yu, T.; Wu, S.; Wyder, L.; Regenass, U.; Hilpert, K.; Huang, M.; Geng, M.; Shen, J. Discovery and optimization of 4,5-diarylisoxazoles as potent dual inhibitors of pyruvate dehydrogenase kinase and heat shock protein 90. J. Med. Chem., 2014, 57, 9832-9843.
Zhou, M.; Ning, C.; Liu, R.; He, Y.; Yu, N. Design, synthesis and biological evaluation of indeno[1,2-d]thiazole derivatives as potent histone deacetylase inhibitors. Bioorg. Med. Chem. Lett., 2013, 23, 3200-3203.
Ning, C.; Bi, Y.; He, Y.; Huang, W.; Liu, L.; Li, Y.; Zhang, S.; Liu, X.; Yu, N. Design, synthesis and biological evaluation of di-substituted cinnamic hydroxamic acids bearing urea/thiourea unit as potent histone deacetylase inhibitors. Bioorg. Med. Chem. Lett., 2013, 23, 6432-6435.
William, A.D.; Lez, A.C.H.; Blanchard, S.; Poulsen, A.; Teo, E.L.; Nagaraj, H.; Tan, E.; Chen, D.; Williams, M.; Sun, E.T.; Goh, K.C.; Ong, W.C.; Goh, S.K.; Hart, S.; Jayaraman, R.; Pasha, M.K.; Ethirajulu, K.; Wood, J.M.; Dymock, B.W. Discovery of the Macrocycle 11-(2-Pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[,6).1(8,12)] heptacosa-1(25),2(26),3, 5,8,10,12(27),16,21,23-decaene (SB1518), a Potent Janus Kinase 2/Fms-Like Tyrosine Kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma. J. Med. Chem., 2011, 54, 4638-4658.
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.
Zhang, X.; Raghavan, S.; Ihnat, M.; Hamel, E.; Zammiello, C.; Bastian, A.; Mooberry, S.L.; Gangjee, A. The design, synthesis and biological evaluation of conformationally restricted 4-substituted-2,6-dimethylfuro[2,3-d]pyrimidines as multi-targeted receptor tyrosine kinase and microtubule inhibitors as potential antitumor agents. Bioorg. Med. Chem., 2015, 23, 2408-2423.
Mahalel, S.; Bharate, S.B.; Manda, S.; Joshi, P.; Jenkins, P.R.; Vishwakarma, R.A.; Chaudhuri, B. Antitumour potential of BPT: a dual inhibitor of cdk4 and tubulin polymerization. Cell Death Dis., 2015, 6, 1743-1755.
Ferlin, M.G.; Chiarelotto, G.; Gasparotto, V.; Dalla Via, L.; Pezzi, V.; Barzon, L.; Palu, G.; Castagliuolo, I. Synthesis and in vitro and in vivo antitumor activity of 2-phenylpyrroloquinolin-4-ones. J. Med. Chem., 2005, 48, 3417-3427.
Gasparotto, V.; Castagliuolo, I.; Chiarelotto, G.; Pezzi, V.; Montanaro, D.; Brun, P.; Palu, G.; Viola, G.; Ferlin, M.G. Synthesis and biological activity of 7-phenyl-6,9-dihydro-3H-pyrrolo[3,2-f] quinolin-9-ones: A new class of antimitotic agents devoid of aromatase activity. J. Med. Chem., 2006, 49, 1910-1915.
Carta, D.; Bortolozzi, R.; Hamel, E.; Basso, G.; Moro, S.; Viola, G.; Ferlin, M.G. Novel 3-substituted 7-phenylpyrrolo[3,2-f]quinolin-9(6H)-ones as single entities with multitarget antiproliferative activity. J. Med. Chem., 2015, 58, 7991-8010.
Cao, R.; Liu, M.; Yin, M.; Liu, Q.; Wang, Y.; Huang, N. Discovery of novel tubulin inhibitors via structure-based hierarchical virtual screening. J. Chem. Inf. Model., 2012, 52, 2730-2740.
Cao, R.; Wang, Y.; Huang, N. Discovery of 2-acylaminothiophene-3-carboxamides as multitarget inhibitors for BCR-ABL kinase and microtubules. J. Chem. Inf. Model., 2015, 55, 2435-2442.
Purwin, M.; Toribio, J.H.; Coderch, C.; Panchuk, R.; Skorokhyd, N.; Filipiak, K.; Pascual-Teresa, B.D.; Ramos, A. Design and synthesis of novel dual-target agents for HDAC1 and CK2 inhibition. RSC Advances, 2016, 6, 66595-66608.
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-hydroxy heptanamide (CUDC-101) as a potent multi-acting HDAC, EGFR, and HER2 inhibitor for the treatment of cancer. J. Med. Chem., 2010, 53, 2000-2009.
Yang, E.G.; Mustafa, N.; Tan, E.C.; Poulsen, A.; Ramanujulu, P.M.; Chng, W.J.; Yen, J.J.Y.; Dymock, B.W. Design and synthesis of Janus Kinase 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, 8233-8262.
Morioka, M. 3-Cyano-6-(5-methyl-3-pyrazoloamino) pyridines (Part 2): A dual inhibitor of Aurora kinase and tubulin polymerization. Bioorg. Med. Chem. Lett., 2016, 26, 5860-5862.
Maira, S.M.; Pecchi, S.; Huamg, A.; Burger, M.; Knapp, M.; Sterker, D.; Schnell, C.; Guthy, D.; Nagal, T.; Wiesmann, M.; Brachmann, S.; Fritsch, C.; Dorsch, M.; Chene, P.; Shoemaker, K.; Pover, A.; Menezes, D.; Martiny Baron, G.; Fabbro, D.; Wilson, C.J.; Schlegel, R.; Hofmann, F.; Garcia Echeverria, C.; Sellers, W.R.; Voliva, C.F. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol. Cancer Ther., 2012, 11, 317-328.
Burger, M.T.; Pecchi, S.; Burger, M.T.; Wagman, A.; Ni, Z.J.; Knapp, M.; Hendrickson, T.; Atallah, G.; Pfister, K.; Zhang, Y.; Bartulis, S.; Frazier, K.; Ng, S.; Smith, A.; Verhagen, J.; Haznedar, J.; Huh, K.; Iwanowicz, E.; Xin, X.; Menezes, D.; Merritt, H.; Lee, I.; Wiesmann, M.; Kaufmann, S.; Crawford, K.; Chin, M.; Bussiere, D.; Shoemaker, K.; Zaror, I.; Maira, S.M.; Voliva, C.F. Identification of NVP-BKM120 as a potent, selective, orally bioavailable class I PI3 kinase inhibitor for treating cancer. ACS Med. Chem. Lett., 2011, 2, 774-779.
Massacesi, C.; Tomaso, E.; Fretault, N.; Hirawat, S. Challenges in the clinical development of PI3K inhibitors. Ann. N. Y. Acad. Sci., 2013, 1280, 19-23.
Saura, C.; Bendell, J.; Jerusalem, G.; Su, S.; Ru, Q.; Buck, S.D.; Mills, D.; Requet, S.; Bosch, A.; Urruticoechea, A.; Beck, J.T.; Tomaso, E.D.; Sternberg, D.W.; Massacesi, C.; Hirawat, S.; Dirix, L.; Baselga, J. Phase Ib study of Buparlisib plus Trastuzumab in patients with HER2-positive advanced or metastatic breast cancer that has progressed on Trastuzumab-based therapy. Clin. Cancer Res., 2014, 20, 1935-1945.
Brachmann, S.M.; Kleylein Sohn, J.; Gaulis, S.; Kauffmann, A.; Blommers, M.J.; Kaziclegueux, M.; Laborde, L.; Hattenberger, M.; Stauffer, F.; Vaxelaire, J.; Romanet, V.; Henry, C.; Maurakami, M.; Guthy, D.A.; Sterker, D.; Bergling, S.; Wilson, C.; Brummendorf, T.; Fritsch, C.; Garcia Echeverria, C.; Sellers, W.R.; Hofmann, F.; Maira, S.M. Characterization of the mechanism of action of the pan class I PI3K inhibitor NVP-BKM120 across a broad range of concentrations. Mol. Cancer Ther., 2012, 11, 1747-1757.
Andrea, E.T.B.; John, E.P.F.B.; Alison, J.B.A.M.; Alexander, M.I.D.R.; Vladimir, C.; Cmiljanovic, N.; Bargsten, K.; Aher, A.; Akhmanova, A.; Dıaz, J.F.; Fabbro, D.; Zvelebil, M.; Roger, L.; Michel, O.W.; Matthias Wymann, P.S. Deconvolution of Buparlisib’s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention. Nat. Commun., 2017, 8, 14683.
Sk, U.K.; Gowda, A.S.; Crampsie, M.A.; Yun, J.K.; Spratt, T.E.; Amin, S.; Sharma, A.K. Development of novel naphthalimide derivatives and their evaluation as potential melanoma therapeutics. Eur. J. Med. Chem., 2011, 46, 3331-3338.
Sharma, A.K.; Sharma, A.; Desai, D.; Madhunapantula, S.V.; Huh, S.J.; Robertson, G.P.; Amin, S. Synthesis and anticancer activity comparison of phenylalkyl isoselenocyanates with corresponding naturally occurring and synthetic isothiocyanates. J. Med. Chem., 2008, 51, 7820-7826.
Karelia, D.N. SK, U.H.; Singh, P.; Gowda, A.S.P.; Pandey, M.K.; Ramisetti, S.R.; Amin, S.; Sharma, A.K.; Design, synthesis, and identification of a novel napthalamideisoselenocyanate compound NISC-6 as a dual Topoisomerase-IIa and Akt pathway inhibitor, and evaluation of its anti-melanoma activity. Eur. J. Med. Chem., 2017, 135, 282-295.
Li, Y.; Luo, X.; Guo, Q.; Nie, Y.; Wang, T.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]pyrimidin-2-yl)amino)phenyl)-N8-hydroxy octanediamide as a novel inhibitor targeting Cyclin-dependent Kinase 4/9 (CDK4/9) and Histone Deacetlyase1 (HDAC1) against malignant cancer. J. Med. Chem., 2018, 61, 3166-3192.
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 combinational treatment of leukemia and invasive fungal infections. J. Med. Chem., 2018, 61(14), 6056-6074.
Trippier, P.C.; Labby, K.J.; Hawker, D.D.; Mataka, J.J.; Silverman, R.B. Target- and mechanism-based therapeutics for neurodegenerative diseases: Strength in numbers. J. Med. Chem., 2013, 56, 3121-3147.
Kinarivala, N.; Patel, R.; Boustany, R.M.; Al-Ahmad, A.; Trippier, P.C. Discovery of aromatic carbamates that confer neuroprotective activity by enhancing autophagy and inducing the anti-apoptotic protein B-Cell lymphoma 2 (Bcl-2). J. Med. Chem., 2017, 60, 9739-9756.
Morphy, R.; Rankovic, Z. Designed multiple ligands. an emerging drug discovery paradigm. J. Med. Chem., 2005, 48, 6523-6543.
Geldenhuys, W.J.; Van der Schyf, C.J. Rationally designed multi-targeted agents against neurodegenerative diseases. Curr. Med. Chem., 2013, 20, 1662-1672.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [842 - 874]
Pages: 33
DOI: 10.2174/1871520619666190118120708
Price: $58

Article Metrics

PDF: 46
PRC: 1