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Current Medicinal Chemistry

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Review Article

A Comprehensive Description of Hypoxia-inducible Factor 2α Inhibitors as Anticancer Agents: A Mini-review

Author(s): Hongyuan Lu, Yan Zhu, Wenwu Liu, Yuanyuan Yan, Xiaowen Jiang, Qinbiao Wang, Yanyun Zhao, Miao He* and Minjie Wei*

Volume 30, Issue 25, 2023

Published on: 18 November, 2022

Page: [2835 - 2849] Pages: 15

DOI: 10.2174/0929867329666220829095334

Price: $65

Abstract

Targeting the tumor microenvironment is a promising strategy to prevent metastasis, overcome acquired drug resistance, and improve the therapeutic effect. Hypoxia is one of the characteristics of the tumor microenvironment, which is mainly regulated by hypoxia-inducible factors. Hypoxia-inducible factors (HIFs) including HIF-1α, HIF-2α, and HIF-3α, of which HIF-2α has assumed a more important role in tumor hypoxia environment. It has been demonstrated that HIF-2α plays an important role in tumor diseases, including renal cell carcinoma, breast cancer, non-small cell lung cancer, and gastric cancer, among others. Therefore, targeting HIF-2α has become one of the important strategies for treating cancers. HIF-2α inhibitors can be divided into two categories: specific inhibitors and non-specific inhibitors. The former includes synthetic monomer compounds and traditional Chinese medicine extracts. In this review, we summarized, classified, and discussed current research on the structure, structure-activity relationship (SAR), and pharmacology of HIF-2α inhibitors, which is helpful to the rational design of effective drugs for various types of malignant tumors.

Keywords: HIF-2α inhibitors, Cancers, Structure-activity relationship (SAR), Hypoxia, Pharmacological activities, Structural modificationHIF-2α inhibitors, Structural modification

« Previous Next »
[1]
Keith, B.; Johnson, R.S.; Simon, M.C. HIF1α and HIF2α: Sibling rivalry in hypoxic tumour growth and progression. Nat. Rev. Cancer, 2011, 12(1), 9-22.
[http://dx.doi.org/10.1038/nrc3183] [PMID: 22169972]
[2]
Kai, A.K.; Chan, L.K.; Lo, R.C.; Lee, J.M.; Wong, C.C.; Wong, J.C.; Ng, I.O. Down-regulation of TIMP2 by HIF-1α/miR-210/HIF-3α regulatory feedback circuit enhances cancer metastasis in hepatocellular carcinoma. Hepatology, 2016, 64(2), 473-487.
[http://dx.doi.org/10.1002/hep.28577] [PMID: 27018975]
[3]
Yang, S.L.; Wu, C.; Xiong, Z.F.; Fang, X. Progress on hypoxia-inducible factor-3: Its structure, gene regulation and biological function (Review). Mol. Med. Rep., 2015, 12(2), 2411-2416.
[http://dx.doi.org/10.3892/mmr.2015.3689] [PMID: 25936862]
[4]
Soni, S.; Padwad, Y.S. HIF-1 in cancer therapy: Two decade long story of a transcription factor. Acta Oncol., 2017, 56(4), 503-515.
[http://dx.doi.org/10.1080/0284186X.2017.1301680] [PMID: 28358664]
[5]
Hahne, M.; Schumann, P.; Mursell, M.; Strehl, C.; Hoff, P.; Buttgereit, F.; Gaber, T. Unraveling the role of hypoxia-inducible factor (HIF)-1α and HIF-2α in the adaption process of human microvascular endothelial cells (HMEC-1) to hypoxia: Redundant HIF-dependent regulation of macrophage migration inhibitory factor. Microvasc. Res., 2018, 116, 34-44.
[http://dx.doi.org/10.1016/j.mvr.2017.09.004] [PMID: 28993199]
[6]
Schöning, J.P.; Monteiro, M.; Gu, W. Drug resistance and cancer stem cells: The shared but distinct roles of hypoxia-inducible factors HIF1α and HIF2α. Clin. Exp. Pharmacol. Physiol., 2017, 44(2), 153-161.
[http://dx.doi.org/10.1111/1440-1681.12693] [PMID: 27809360]
[7]
Zhao, J.; Du, F.; Luo, Y.; Shen, G.; Zheng, F.; Xu, B. The emerging role of hypoxia-inducible factor-2 involved in chemo/radioresistance in solid tumors. Cancer Treat. Rev., 2015, 41(7), 623-633.
[http://dx.doi.org/10.1016/j.ctrv.2015.05.004] [PMID: 25981453]
[8]
Covello, K.L.; Simon, M.C.; Keith, B. Targeted replacement of hypoxia-inducible factor-1alpha by a hypoxia-inducible factor-2alpha knock-in allele promotes tumor growth. Cancer Res., 2005, 65(6), 2277-2286.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-3246] [PMID: 15781641]
[9]
Courtney, K.D.; Ma, Y.; Diaz de Leon, A.; Christie, A.; Xie, Z.; Woolford, L.; Singla, N.; Joyce, A.; Hill, H.; Madhuranthakam, A.J.; Yuan, Q.; Xi, Y.; Zhang, Y.; Chang, J.; Fatunde, O.; Arriaga, Y.; Frankel, A.E.; Kalva, S.; Zhang, S.; McKenzie, T.; Reig Torras, O.; Figlin, R.A.; Rini, B.I.; McKay, R.M.; Kapur, P.; Wang, T.; Pedrosa, I.; Brugarolas, J. HIF-2 complex dissociation, target inhibition, and acquired resistance with PT2385, a first-in-class HIF-2 inhibitor, in patients with clear cell renal cell carcinoma. Clin. Cancer Res., 2020, 26(4), 793-803.
[http://dx.doi.org/10.1158/1078-0432.CCR-19-1459] [PMID: 31727677]
[10]
Murugesan, T.; Rajajeyabalachandran, G.; Kumar, S.; Nagaraju, S.; Jegatheesan, S.K. Targeting HIF-2α as therapy for advanced cancers. Drug Discov. Today, 2018, 23(7), 1444-1451.
[http://dx.doi.org/10.1016/j.drudis.2018.05.003] [PMID: 29753878]
[11]
Koury, M.J.; Haase, V.H. Anaemia in kidney disease: Harnessing hypoxia responses for therapy. Nat. Rev. Nephrol., 2015, 11(7), 394-410.
[http://dx.doi.org/10.1038/nrneph.2015.82] [PMID: 26055355]
[12]
Wallace, E.M.; Rizzi, J.P.; Han, G.; Wehn, P.M.; Cao, Z.; Du, X.; Cheng, T.; Czerwinski, R.M.; Dixon, D.D.; Goggin, B.S.; Grina, J.A.; Halfmann, M.M.; Maddie, M.A.; Olive, S.R.; Schlachter, S.T.; Tan, H.; Wang, B.; Wang, K.; Xie, S.; Xu, R.; Yang, H.; Josey, J.A. A small-molecule antagonist of HIF2α is efficacious in preclinical models of renal cell carcinoma. Cancer Res., 2016, 76(18), 5491-5500.
[http://dx.doi.org/10.1158/0008-5472.CAN-16-0473] [PMID: 27635045]
[13]
Cowman, S.J.; Koh, M.Y. Revisiting the HIF switch in the tumor and its immune microenvironment. Trends Cancer, 2022, 8(1), 28-42.
[http://dx.doi.org/10.1016/j.trecan.2021.10.004] [PMID: 34743924]
[14]
Masoud, G.N.; Li, W. HIF-1α pathway: Role, regulation and intervention for cancer therapy. Acta Pharm. Sin. B, 2015, 5(5), 378-389.
[http://dx.doi.org/10.1016/j.apsb.2015.05.007] [PMID: 26579469]
[15]
Gunton, J.E. Hypoxia-inducible factors and diabetes. J. Clin. Invest., 2020, 130(10), 5063-5073.
[http://dx.doi.org/10.1172/JCI137556] [PMID: 32809974]
[16]
Schödel, J.; Grampp, S.; Maher, E.R.; Moch, H.; Ratcliffe, P.J.; Russo, P.; Mole, D.R. Hypoxia, hypoxia-inducible transcription factors, and renal cancer. Eur. Urol., 2016, 69(4), 646-657.
[http://dx.doi.org/10.1016/j.eururo.2015.08.007] [PMID: 26298207]
[17]
Zhu, W.J.; Li, P.; Wang, L.; Xu, Y.C. Hypoxia-inducible factor-1: A potential pharmacological target to manage psoriasis. Int. Immunopharmacol., 2020, 86, 106689.
[http://dx.doi.org/10.1016/j.intimp.2020.106689] [PMID: 32585606]
[18]
Asgari, R.; Yarani, R.; Mohammadi, P.; Emami Aleagha, M.S. HIF-1α in the crosstalk between reactive oxygen species and autophagy process: A review in multiple sclerosis. Cell. Mol. Neurobiol., 2021.
[http://dx.doi.org/10.1007/s10571-021-01111-5] [PMID: 34089426]
[19]
Martínez-Sáez, O.; Gajate Borau, P.; Alonso-Gordoa, T.; Molina-Cerrillo, J.; Grande, E. Targeting HIF-2 α in clear cell renal cell carcinoma: A promising therapeutic strategy. Crit. Rev. Oncol. Hematol., 2017, 111, 117-123.
[http://dx.doi.org/10.1016/j.critrevonc.2017.01.013] [PMID: 28259286]
[20]
Yu, Y.; Yu, Q.; Zhang, X. Allosteric inhibition of HIF-2α as a novel therapy for clear cell renal cell carcinoma. Drug Discov. Today, 2019, 24(12), 2332-2340.
[http://dx.doi.org/10.1016/j.drudis.2019.09.008] [PMID: 31541711]
[21]
Befani, C.; Liakos, P. The role of hypoxia-inducible factor-2 alpha in angiogenesis. J. Cell. Physiol., 2018, 233(12), 9087-9098.
[http://dx.doi.org/10.1002/jcp.26805] [PMID: 29968905]
[22]
Scheuermann, T.H.; Yang, J.; Zhang, L.; Gardner, K.H.; Bruick, R.K. Hypoxia-inducible factors Per/ARNT/Sim domains: Structure and function. Methods Enzymol., 2007, 435, 3-24.
[http://dx.doi.org/10.1016/S0076-6879(07)35001-5] [PMID: 17998046]
[23]
Gordan, J.D.; Simon, M.C. Hypoxia-inducible factors: Central regulators of the tumor phenotype. Curr. Opin. Genet. Dev., 2007, 17(1), 71-77.
[http://dx.doi.org/10.1016/j.gde.2006.12.006] [PMID: 17208433]
[24]
Erbel, P.J.; Card, P.B.; Karakuzu, O.; Bruick, R.K.; Gardner, K.H. Structural basis for PAS domain heterodimerization in the basic helix loop helix-PAS transcription factor hypoxia-inducible factor. Proc. Natl. Acad. Sci. USA, 2003, 100(26), 15504-15509.
[http://dx.doi.org/10.1073/pnas.2533374100] [PMID: 14668441]
[25]
Card, P.B.; Erbel, P.J.; Gardner, K.H. Structural basis of ARNT PAS-B dimerization: use of a common beta-sheet interface for hetero- and homodimerization. J. Mol. Biol., 2005, 353(3), 664-677.
[http://dx.doi.org/10.1016/j.jmb.2005.08.043] [PMID: 16181639]
[26]
Key, J.; Scheuermann, T.H.; Anderson, P.C.; Daggett, V.; Gardner, K.H. Principles of ligand binding within a completely buried cavity in HIF2alpha PAS-B. J. Am. Chem. Soc., 2009, 131(48), 17647-17654.
[http://dx.doi.org/10.1021/ja9073062] [PMID: 19950993]
[27]
Scheuermann, T.H.; Li, Q.; Ma, H.W.; Key, J.; Zhang, L.; Chen, R.; Garcia, J.A.; Naidoo, J.; Longgood, J.; Frantz, D.E.; Tambar, U.K.; Gardner, K.H.; Bruick, R.K. Allosteric inhibition of hypoxia inducible factor-2 with small molecules. Nat. Chem. Biol., 2013, 9(4), 271-276.
[http://dx.doi.org/10.1038/nchembio.1185] [PMID: 23434853]
[28]
McDonald, W.; Funatogawa, C.; Li, Y.; Szundi, I.; Chen, Y.; Fee, J.A.; Stout, C.D.; Einarsdóttir, Ó. Ligand access to the active site in Thermus thermophilus ba(3) and bovine heart aa(3) cytochrome oxidases. Biochemistry, 2013, 52(4), 640-652.
[http://dx.doi.org/10.1021/bi301358a] [PMID: 23282175]
[29]
Linehan, W.M.; Schmidt, L.S.; Crooks, D.R.; Wei, D.; Srinivasan, R.; Lang, M.; Ricketts, C.J. The metabolic basis of kidney cancer. Cancer Discov., 2019, 9(8), 1006-1021.
[http://dx.doi.org/10.1158/2159-8290.CD-18-1354] [PMID: 31088840]
[30]
Shuch, B.; Amin, A.; Armstrong, A.J.; Eble, J.N.; Ficarra, V.; Lopez-Beltran, A.; Martignoni, G.; Rini, B.I.; Kutikov, A. Understanding pathologic variants of renal cell carcinoma: Distilling therapeutic opportunities from biologic complexity. Eur. Urol., 2015, 67(1), 85-97.
[http://dx.doi.org/10.1016/j.eururo.2014.04.029] [PMID: 24857407]
[31]
Hsieh, J.J.; Purdue, M.P.; Signoretti, S.; Swanton, C.; Albiges, L.; Schmidinger, M.; Heng, D.Y.; Larkin, J.; Ficarra, V. Renal cell carcinoma. Nat. Rev. Dis. Primers, 2017, 3, 17009.
[http://dx.doi.org/10.1038/nrdp.2017.9] [PMID: 28276433]
[32]
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature, 2013, 499(7456), 43-49.
[http://dx.doi.org/10.1038/nature12222] [PMID: 23792563]
[33]
Kaelin, W.G., Jr. The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer. Nat. Rev. Cancer, 2008, 8(11), 865-873.
[http://dx.doi.org/10.1038/nrc2502] [PMID: 18923434]
[34]
Ivan, M.; Kondo, K.; Yang, H.; Kim, W.; Valiando, J.; Ohh, M.; Salic, A.; Asara, J.M.; Lane, W.S.; Kaelin, W.G., Jr. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: Implications for O2 sensing. Science, 2001, 292(5516), 464-468.
[http://dx.doi.org/10.1126/science.1059817] [PMID: 11292862]
[35]
Murakami, A.; Wang, L.; Kalhorn, S.; Schraml, P.; Rathmell, W.K.; Tan, A.C.; Nemenoff, R.; Stenmark, K.; Jiang, B.H.; Reyland, M.E.; Heasley, L.; Hu, C.J. Context-dependent role for chromatin remodeling component PBRM1/BAF180 in clear cell renal cell carcinoma. Oncogenesis, 2017, 6(1), e287.
[http://dx.doi.org/10.1038/oncsis.2016.89] [PMID: 28092369]
[36]
Biswas, S.; Troy, H.; Leek, R.; Chung, Y.L.; Li, J.L.; Raval, R.R.; Turley, H.; Gatter, K.; Pezzella, F.; Griffiths, J.R.; Stubbs, M.; Harris, A.L. Effects of HIF-1alpha and HIF2alpha on growth and metabolism of clear-cell renal cell carcinoma 786-0 xenografts. J. Oncol., 2010, 2010, 757908.
[http://dx.doi.org/10.1155/2010/757908] [PMID: 20652061]
[37]
Maranchie, J.K.; Vasselli, J.R.; Riss, J.; Bonifacino, J.S.; Linehan, W.M.; Klausner, R.D. The contribution of VHL substrate binding and HIF1-alpha to the phenotype of VHL loss in renal cell carcinoma. Cancer Cell, 2002, 1(3), 247-255.
[http://dx.doi.org/10.1016/S1535-6108(02)00044-2] [PMID: 12086861]
[38]
Raval, R.R.; Lau, K.W.; Tran, M.G.; Sowter, H.M.; Mandriota, S.J.; Li, J.L.; Pugh, C.W.; Maxwell, P.H.; Harris, A.L.; Ratcliffe, P.J. Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Mol. Cell. Biol., 2005, 25(13), 5675-5686.
[http://dx.doi.org/10.1128/MCB.25.13.5675-5686.2005] [PMID: 15964822]
[39]
Kondo, K.; Klco, J.; Nakamura, E.; Lechpammer, M.; Kaelin, W.G., Jr. Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell, 2002, 1(3), 237-246.
[http://dx.doi.org/10.1016/S1535-6108(02)00043-0] [PMID: 12086860]
[40]
Kondo, K.; Kim, W.Y.; Lechpammer, M.; Kaelin, W.G., Jr. Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth. PLoS Biol., 2003, 1(3), E83.
[http://dx.doi.org/10.1371/journal.pbio.0000083] [PMID: 14691554]
[41]
Shinojima, T.; Oya, M.; Takayanagi, A.; Mizuno, R.; Shimizu, N.; Murai, M. Renal cancer cells lacking hypoxia inducible factor (HIF)-1alpha expression maintain vascular endothelial growth factor expression through HIF-2alpha. Carcinogenesis, 2007, 28(3), 529-536.
[http://dx.doi.org/10.1093/carcin/bgl143] [PMID: 16920734]
[42]
Pharmaceuticals. FDA Approves Merck's hypoxia-inducible factor-2 alpha inhibitor WELIREG for the treatment of patients with certain types of von hippel-lindau disease-associated tumors. Available from: https://investingnews.com/news/pharmaceutical-investing/fda-approves-mercks-hypoxia-inducible-factor-2-alpha-inhibitor-welireg-for-the-treatment-of-patients-with-certain-types-of-von-hippel-lindau-disease-associated-tumors/
[43]
Regan Anderson, T.M.; Peacock, D.L.; Daniel, A.R.; Hubbard, G.K.; Lofgren, K.A.; Girard, B.J.; Schörg, A.; Hoogewijs, D.; Wenger, R.H.; Seagroves, T.N.; Lange, C.A. Breast tumor kinase (Brk/PTK6) is a mediator of hypoxia-associated breast cancer progression. Cancer Res., 2013, 73(18), 5810-5820.
[http://dx.doi.org/10.1158/0008-5472.CAN-13-0523] [PMID: 23928995]
[44]
Helczynska, K.; Larsson, A.M.; Holmquist Mengelbier, L.; Bridges, E.; Fredlund, E.; Borgquist, S.; Landberg, G.; Påhlman, S.; Jirström, K. Hypoxia-inducible factor-2alpha correlates to distant recurrence and poor outcome in invasive breast cancer. Cancer Res., 2008, 68(22), 9212-9220.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-1135] [PMID: 19010893]
[45]
Yan, Y.; Liu, F.; Han, L.; Zhao, L.; Chen, J.; Olopade, O.I.; He, M.; Wei, M. HIF-2α promotes conversion to a stem cell phenotype and induces chemoresistance in breast cancer cells by activating Wnt and Notch pathways. J. Exp. Clin. Cancer Res., 2018, 37(1), 256.
[http://dx.doi.org/10.1186/s13046-018-0925-x] [PMID: 30340507]
[46]
Yan, Y.; He, M.; Zhao, L.; Wu, H.; Zhao, Y.; Han, L.; Wei, B.; Ye, D.; Lv, X.; Wang, Y.; Yao, W.; Zhao, H.; Chen, B.; Jin, Z.; Wen, J.; Zhu, Y.; Yu, T.; Jin, F.; Wei, M. A novel HIF-2α targeted inhibitor suppresses hypoxia-induced breast cancer stemness via SOD2-mtROS-PDI/GPR78-UPRER axis. Cell Death Differ., 2022.
[http://dx.doi.org/10.1038/s41418-022-00963-8] [PMID: 35301432]
[47]
Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer Statistics, 2021. CA Cancer J. Clin., 2021, 71(1), 7-33.
[http://dx.doi.org/10.3322/caac.21654] [PMID: 33433946]
[48]
Wu, X.H.; Qian, C.; Yuan, K. Correlations of hypoxia-inducible factor-1α/hypoxia-inducible factor-2α expression with angiogenesis factors expression and prognosis in non-small cell lung cancer. Chin. Med. J. (Engl.), 2011, 124(1), 11-18.
[PMID: 21362301]
[49]
Luan, Y.; Gao, C.; Miao, Y.; Li, Y.; Wang, Z.; Qiu, X. Clinicopathological and prognostic significance of HIF-1α and HIF-2α expression in small cell lung cancer. Pathol. Res. Pract., 2013, 209(3), 184-189.
[http://dx.doi.org/10.1016/j.prp.2012.10.017] [PMID: 23375698]
[50]
Mazumdar, J.; Hickey, M.M.; Pant, D.K.; Durham, A.C.; Sweet-Cordero, A.; Vachani, A.; Jacks, T.; Chodosh, L.A.; Kissil, J.L.; Simon, M.C.; Keith, B. HIF-2alpha deletion promotes Kras-driven lung tumor development. Proc. Natl. Acad. Sci. USA, 2010, 107(32), 14182-14187.
[http://dx.doi.org/10.1073/pnas.1001296107] [PMID: 20660313]
[51]
Zhen, Q.; Liu, J.F.; Liu, J.B.; Wang, R.F.; Chu, W.W.; Zhang, Y.X.; Tan, G.L.; Zhao, X.J.; Lv, B.L. Endothelial PAS domain-containing protein 1 confers TKI-resistance by mediating EGFR and MET pathways in non-small cell lung cancer cells. Cancer Biol. Ther., 2015, 16(4), 549-557.
[http://dx.doi.org/10.1080/15384047.2015.1016689] [PMID: 25831463]
[52]
Pandey, N.; Tyagi, G.; Kaur, P.; Pradhan, S.; Rajam, M.V.; Srivastava, T. Allicin overcomes hypoxia mediated cisplatin resistance in lung cancer cells through ros mediated cell death pathway and by suppressing hypoxia inducible factors. Cell. Physiol. Biochem., 2020, 54(4), 748-766.
[53]
Park, S.K.; Dadak, A.M.; Haase, V.H.; Fontana, L.; Giaccia, A.J.; Johnson, R.S. Hypoxia-induced gene expression occurs solely through the action of hypoxia-inducible factor 1alpha (HIF-1alpha): Role of cytoplasmic trapping of HIF-2alpha. Mol. Cell. Biol., 2003, 23(14), 4959-4971.
[http://dx.doi.org/10.1128/MCB.23.14.4959-4971.2003] [PMID: 12832481]
[54]
Song, I.S.; Wang, A.G.; Yoon, S.Y.; Kim, J.M.; Kim, J.H.; Lee, D.S.; Kim, N.S. Regulation of glucose metabolism-related genes and VEGF by HIF-1 alpha and HIF-1 beta, but not HIF-2 alpha, in gastric cancer. Exp. Mol. Med., 2009, 41(1), 51-58.
[http://dx.doi.org/10.3858/emm.2009.41.1.007] [PMID: 19287200]
[55]
Wang, Y.; Li, Z.; Zhang, H.; Jin, H.; Sun, L.; Dong, H.; Xu, M.; Zhao, P.; Zhang, B.; Wang, J.; Pan, Y.; Liu, L. HIF-1α and HIF-2α correlate with migration and invasion in gastric cancer. Cancer Biol. Ther., 2010, 10(4), 376-382.
[http://dx.doi.org/10.4161/cbt.10.4.12441] [PMID: 20559021]
[56]
Tong, W.W.; Tong, G.H.; Chen, X.X.; Zheng, H.C.; Wang, Y.Z. HIF2α is associated with poor prognosis and affects the expression levels of survivin and cyclin D1 in gastric carcinoma. Int. J. Oncol., 2015, 46(1), 233-242.
[http://dx.doi.org/10.3892/ijo.2014.2719] [PMID: 25338835]
[57]
Wang, Y.; Wang, X.; Su, X.; Liu, T. HIF-2α affects proliferation and apoptosis of MG-63 osteosarcoma cells through MAPK signaling. Mol. Med. Rep., 2017, 15(4), 2174-2178.
[http://dx.doi.org/10.3892/mmr.2017.6243] [PMID: 28259908]
[58]
Yang, J.; Zhang, X.; Zhang, Y.; Zhu, D.; Zhang, L.; Li, Y.; Zhu, Y.; Li, D.; Zhou, J. HIF-2α promotes epithelial-mesenchymal transition through regulating Twist2 binding to the promoter of E-cadherin in pancreatic cancer. J. Exp. Clin. Cancer Res., 2016, 35, 26.
[http://dx.doi.org/10.1186/s13046-016-0298-y] [PMID: 26842802]
[59]
Raspaglio, G.; Petrillo, M.; Martinelli, E.; Li Puma, D.D.; Mariani, M.; De Donato, M.; Filippetti, F.; Mozzetti, S.; Prislei, S.; Zannoni, G.F.; Scambia, G.; Ferlini, C. Sox9 and Hif-2α regulate TUBB3 gene expression and affect ovarian cancer aggressiveness. Gene, 2014, 542(2), 173-181.
[http://dx.doi.org/10.1016/j.gene.2014.03.037] [PMID: 24661907]
[60]
Scheuermann, T.H.; Tomchick, D.R.; Machius, M.; Guo, Y.; Bruick, R.K.; Gardner, K.H. Artificial ligand binding within the HIF2alpha PAS-B domain of the HIF2 transcription factor. Proc. Natl. Acad. Sci. USA, 2009, 106(2), 450-455.
[http://dx.doi.org/10.1073/pnas.0808092106] [PMID: 19129502]
[61]
Woldemichael, G.M.; Vasselli, J.R.; Gardella, R.S.; McKee, T.C.; Linehan, W.M.; McMahon, J.B. Development of a cell-based reporter assay for screening of inhibitors of hypoxia-inducible factor 2-induced gene expression. J. Biomol. Screen., 2006, 11(6), 678-687.
[http://dx.doi.org/10.1177/1087057106289234] [PMID: 16858007]
[62]
Grkovic, T.; Whitson, E.L.; Rabe, D.C.; Gardella, R.S.; Bottaro, D.P.; Linehan, W.M.; McMahon, J.B.; Gustafson, K.R.; McKee, T.C. Identification and evaluation of soft coral diterpenes as inhibitors of HIF-2α induced gene expression. Bioorg. Med. Chem. Lett., 2011, 21(7), 2113-2115.
[http://dx.doi.org/10.1016/j.bmcl.2011.01.127] [PMID: 21353547]
[63]
Scheuermann, T.H.; Stroud, D.; Sleet, C.E.; Bayeh, L.; Shokri, C.; Wang, H.; Caldwell, C.G.; Longgood, J.; MacMillan, J.B.; Bruick, R.K.; Gardner, K.H.; Tambar, U.K. Isoform-selective and stereoselective inhibition of hypoxia inducible factor-2. J. Med. Chem., 2015, 58(15), 5930-5941.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00529] [PMID: 26226049]
[64]
Ullman, E.F.; Kirakossian, H.; Switchenko, A.C.; Ishkanian, J.; Ericson, M.; Wartchow, C.A.; Pirio, M.; Pease, J.; Irvin, B.R.; Singh, S.; Singh, R.; Patel, R.; Dafforn, A.; Davalian, D.; Skold, C.; Kurn, N.; Wagner, D.B. Luminescent oxygen channeling assay (LOCI): sensitive, broadly applicable homogeneous immunoassay method. Clin. Chem., 1996, 42(9), 1518-1526.
[http://dx.doi.org/10.1093/clinchem/42.9.1518] [PMID: 8787723]
[65]
Wehn, P.M.; Rizzi, J.P.; Dixon, D.D.; Grina, J.A.; Schlachter, S.T.; Wang, B.; Xu, R.; Yang, H.; Du, X.; Han, G.; Wang, K.; Cao, Z.; Cheng, T.; Czerwinski, R.M.; Goggin, B.S.; Huang, H.; Halfmann, M.M.; Maddie, M.A.; Morton, E.L.; Olive, S.R.; Tan, H.; Xie, S.; Wong, T.; Josey, J.A.; Wallace, E.M. Design and activity of specific hypoxia-inducible factor-2α (HIF-2α) inhibitors for the treatment of clear cell renal cell carcinoma: Discovery of clinical candidate (S)-3-((2,2-Difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1 H-inden-4-yl)oxy)-5-fluorobenzonitrile (PT2385). J. Med. Chem., 2018, 61(21), 9691-9721.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01196] [PMID: 30289716]
[66]
Rogers, J.L.; Bayeh, L.; Scheuermann, T.H.; Longgood, J.; Key, J.; Naidoo, J.; Melito, L.; Shokri, C.; Frantz, D.E.; Bruick, R.K.; Gardner, K.H.; MacMillan, J.B.; Tambar, U.K. Development of inhibitors of the PAS-B domain of the HIF-2α transcription factor. J. Med. Chem., 2013, 56(4), 1739-1747.
[http://dx.doi.org/10.1021/jm301847z] [PMID: 23363003]
[67]
Cho, H.; Du, X.; Rizzi, J.P.; Liberzon, E.; Chakraborty, A.A.; Gao, W.; Carvo, I.; Signoretti, S.; Bruick, R.K.; Josey, J.A.; Wallace, E.M.; Kaelin, W.G. On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models. Nature, 2016, 539(7627), 107-111.
[http://dx.doi.org/10.1038/nature19795] [PMID: 27595393]
[68]
Chen, W.; Hill, H.; Christie, A.; Kim, M.S.; Holloman, E.; Pavia-Jimenez, A.; Homayoun, F.; Ma, Y.; Patel, N.; Yell, P.; Hao, G.; Yousuf, Q.; Joyce, A.; Pedrosa, I.; Geiger, H.; Zhang, H.; Chang, J.; Gardner, K.H.; Bruick, R.K.; Reeves, C.; Hwang, T.H.; Courtney, K.; Frenkel, E.; Sun, X.; Zojwalla, N.; Wong, T.; Rizzi, J.P.; Wallace, E.M.; Josey, J.A.; Xie, Y.; Xie, X.J.; Kapur, P.; McKay, R.M.; Brugarolas, J. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature, 2016, 539(7627), 112-117.
[http://dx.doi.org/10.1038/nature19796] [PMID: 27595394]
[69]
Xu, R.; Wang, K.; Rizzi, J.P.; Huang, H.; Grina, J.A.; Schlachter, S.T.; Wang, B.; Wehn, P.M.; Yang, H.; Dixon, D.D.; Czerwinski, R.M.; Du, X.; Ged, E.L.; Han, G.; Tan, H.; Wong, T.; Xie, S.; Josey, J.A.; Wallace, E.M. 3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977), a hypoxia-inducible factor 2α (HIF-2α) inhibitor for the treatment of clear cell renal cell carcinoma. J. Med. Chem., 2019, 62(15), 6876-6893.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00719] [PMID: 31282155]
[70]
Deeks, E.D. Belzutifan: First approval. Drugs, 2021, 81(16), 1921-1927.
[http://dx.doi.org/10.1007/s40265-021-01606-x] [PMID: 34613603]
[71]
Yu, T.; Tang, B.; Sun, X. Development of inhibitors targeting hypoxia-inducible factor 1 and 2 for cancer therapy. Yonsei Med. J., 2017, 58(3), 489-496.
[http://dx.doi.org/10.3349/ymj.2017.58.3.489] [PMID: 28332352]
[72]
Chong, W.; Li, Y.; Liu, B.; Liu, Z.; Zhao, T.; Wonsey, D.R.; Chen, C.; Velmahos, G.C.; deMoya, M.A.; King, D.R.; Kung, A.L.; Alam, H.B. Anti-inflammatory properties of histone deacetylase inhibitors: A mechanistic study. J. Trauma Acute Care Surg., 2012, 72(2), 347-353.
[http://dx.doi.org/10.1097/TA.0b013e318243d8b2] [PMID: 22327976]
[73]
Chintala, S.; Najrana, T.; Toth, K.; Cao, S.; Durrani, F.A.; Pili, R.; Rustum, Y.M. Prolyl hydroxylase 2 dependent and Von-Hippel-Lindau independent degradation of Hypoxia-inducible factor 1 and 2 alpha by selenium in clear cell renal cell carcinoma leads to tumor growth inhibition. BMC Cancer, 2012, 12, 293.
[http://dx.doi.org/10.1186/1471-2407-12-293] [PMID: 22804960]
[74]
Kong, H.S.; Lee, S.; Beebe, K.; Scroggins, B.; Gupta, G.; Lee, M.J.; Jung, Y.J.; Trepel, J.; Neckers, L. Emetine promotes von Hippel-Lindau-independent degradation of hypoxia-inducible factor-2α in clear cell renal carcinoma. Mol. Pharmacol., 2010, 78(6), 1072-1078.
[http://dx.doi.org/10.1124/mol.110.066514] [PMID: 20813864]
[75]
Guan, Y.; Reddy, K.R.; Zhu, Q.; Li, Y.; Lee, K.; Weerasinghe, P.; Prchal, J.; Semenza, G.L.; Jing, N. G-rich oligonucleotides inhibit HIF-1alpha and HIF-2alpha and block tumor growth. Mol. Ther., 2010, 18(1), 188-197.
[http://dx.doi.org/10.1038/mt.2009.219] [PMID: 19755960]
[76]
Joshi, S.; Singh, A.R.; Durden, D.L. Pan-PI-3 kinase inhibitor SF1126 shows antitumor and antiangiogenic activity in renal cell carcinoma. Cancer Chemother. Pharmacol., 2015, 75(3), 595-608.
[http://dx.doi.org/10.1007/s00280-014-2639-x] [PMID: 25578041]
[77]
Viziteu, E.; Grandmougin, C.; Goldschmidt, H.; Seckinger, A.; Hose, D.; Klein, B.; Moreaux, J. Chetomin, targeting HIF-1α/p300 complex, exhibits antitumour activity in multiple myeloma. Br. J. Cancer, 2016, 114(5), 519-523.
[http://dx.doi.org/10.1038/bjc.2016.20] [PMID: 26867162]
[78]
Befani, C.D.; Vlachostergios, P.J.; Hatzidaki, E.; Patrikidou, A.; Bonanou, S.; Simos, G.; Papandreou, C.N.; Liakos, P. Bortezomib represses HIF-1α protein expression and nuclear accumulation by inhibiting both PI3K/Akt/TOR and MAPK pathways in prostate cancer cells. J. Mol. Med. (Berl.), 2012, 90(1), 45-54.
[http://dx.doi.org/10.1007/s00109-011-0805-8] [PMID: 21909688]
[79]
Liu, Y.V.; Baek, J.H.; Zhang, H.; Diez, R.; Cole, R.N.; Semenza, G.L. RACK1 competes with HSP90 for binding to HIF-1alpha and is required for O2-independent and HSP90 inhibitor-induced degradation of HIF-1alpha. Mol. Cell, 2007, 25(2), 207-217.
[http://dx.doi.org/10.1016/j.molcel.2007.01.001] [PMID: 17244529]
[80]
Gaur, S.; Wang, Y.; Kretzner, L.; Chen, L.; Yen, T.; Wu, X.; Yuan, Y.C.; Davis, M.; Yen, Y. Pharmacodynamic and pharmacogenomic study of the nanoparticle conjugate of camptothecin CRLX101 for the treatment of cancer. Nanomedicine, 2014, 10(7), 1477-1486.
[http://dx.doi.org/10.1016/j.nano.2014.04.003] [PMID: 24768630]
[81]
Piret, B.; Piette, J. Topoisomerase poisons activate the transcription factor NF-kappaB in ACH-2 and CEM cells. Nucleic Acids Res., 1996, 24(21), 4242-4248.
[http://dx.doi.org/10.1093/nar/24.21.4242] [PMID: 8932379]
[82]
Zhang, H.; Qian, D.Z.; Tan, Y.S.; Lee, K.; Gao, P.; Ren, Y.R.; Rey, S.; Hammers, H.; Chang, D.; Pili, R.; Dang, C.V.; Liu, J.O.; Semenza, G.L. Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth. Proc. Natl. Acad. Sci. USA, 2008, 105(50), 19579-19586.
[http://dx.doi.org/10.1073/pnas.0809763105] [PMID: 19020076]
[83]
Winnicka, K.; Bielawski, K.; Bielawska, A.; Surazyński, A. Antiproliferative activity of derivatives of ouabain, digoxin and proscillaridin A in human MCF-7 and MDA-MB-231 breast cancer cells. Biol. Pharm. Bull., 2008, 31(6), 1131-1140.
[http://dx.doi.org/10.1248/bpb.31.1131] [PMID: 18520043]
[84]
Knowles, H.J.; Raval, R.R.; Harris, A.L.; Ratcliffe, P.J. Effect of ascorbate on the activity of hypoxia-inducible factor in cancer cells. Cancer Res., 2003, 63(8), 1764-1768.
[PMID: 12702559]
[85]
Gao, P.; Zhang, H.; Dinavahi, R.; Li, F.; Xiang, Y.; Raman, V.; Bhujwalla, Z.M.; Felsher, D.W.; Cheng, L.; Pevsner, J.; Lee, L.A.; Semenza, G.L.; Dang, C.V. HIF-dependent antitumorigenic effect of antioxidants in vivo. Cancer Cell, 2007, 12(3), 230-238.
[http://dx.doi.org/10.1016/j.ccr.2007.08.004] [PMID: 17785204]
[86]
Bae, M.K.; Kim, S.H.; Jeong, J.W.; Lee, Y.M.; Kim, H.S.; Kim, S.R.; Yun, I.; Bae, S.K.; Kim, K.W. Curcumin inhibits hypoxia-induced angiogenesis via down-regulation of HIF-1. Oncol. Rep., 2006, 15(6), 1557-1562.
[http://dx.doi.org/10.3892/or.15.6.1557] [PMID: 16685395]
[87]
Choi, H.; Chun, Y.S.; Kim, S.W.; Kim, M.S.; Park, J.W. Curcumin inhibits hypoxia-inducible factor-1 by degrading aryl hydrocarbon receptor nuclear translocator: A mechanism of tumor growth inhibition. Mol. Pharmacol., 2006, 70(5), 1664-1671.
[http://dx.doi.org/10.1124/mol.106.025817] [PMID: 16880289]
[88]
Lee, K.; Qian, D.Z.; Rey, S.; Wei, H.; Liu, J.O.; Semenza, G.L. Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells. Proc. Natl. Acad. Sci. USA, 2009, 106(7), 2353-2358.
[http://dx.doi.org/10.1073/pnas.0812801106] [PMID: 19168635]
[89]
Kong, D.; Park, E.J.; Stephen, A.G.; Calvani, M.; Cardellina, J.H.; Monks, A.; Fisher, R.J.; Shoemaker, R.H.; Melillo, G. Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Res., 2005, 65(19), 9047-9055.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-1235] [PMID: 16204079]
[90]
Palayoor, S.T.; Tofilon, P.J.; Coleman, C.N. Ibuprofen-mediated reduction of hypoxia-inducible factors HIF-1alpha and HIF-2alpha in prostate cancer cells. Clin. Cancer Res., 2003, 9(8), 3150-3157.
[PMID: 12912967]
[91]
Mylonis, I.; Lakka, A.; Tsakalof, A.; Simos, G. The dietary flavonoid kaempferol effectively inhibits HIF-1 activity and hepatoma cancer cell viability under hypoxic conditions. Biochem. Biophys. Res. Commun., 2010, 398(1), 74-78.
[http://dx.doi.org/10.1016/j.bbrc.2010.06.038] [PMID: 20558139]
[92]
Mysore, V.S.; Szablowski, J.; Dervan, P.B.; Frost, P.J. A DNA-binding molecule targeting the adaptive hypoxic response in multiple myeloma has potent antitumor activity. Mol. Cancer Res., 2016, 14(3), 253-266.
[http://dx.doi.org/10.1158/1541-7786.MCR-15-0361] [PMID: 26801054]

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