1,073
Views
16
CrossRef citations to date
0
Altmetric
Review

Hypoxia-inducible factor (HIF) inhibitors: a patent survey (2016–2020)

ORCID Icon, & ORCID Icon
Pages 387-397 | Received 29 Sep 2020, Accepted 06 Jan 2021, Published online: 29 Jan 2021

References

  • Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3(10):721–732.
  • Ohh M, Park CW, Ivan M, et al. Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-lindau protein. Nat Cell Biol. 2000;2(7):423–427.
  • Ivan M, Kondo K, Yang H, et al. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292(5516):464–468.
  • Hewitson KS, McNeill LA, Riordan MV, et al. Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. J Biol Chem. 2002;277(29):26351–26355.
  • Strowitzki MJ, Cummins EP, Taylor CT. Protein hydroxylation by hypoxia-inducible factor (HIF) hydroxylases: unique or ubiquitous? Cells. 2019;8(5):384.
  • Semenza GL. Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu Rev Pathol. 2014;9:47–71.
  • Semenza GLHIF. 1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol. 2000;88(4):1474–1480.
  • Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell. 2012;148(3):399–408.
  • Giaccia A, Siim BG, Johnson RSHIF. 1 as a target for drug development. Nat Rev Drug Discov. 2003;2(10):803–811.
  • Semenza GL, Agani F, Feldser D, et al. Hypoxia, HIF-1, and the pathophysiology of common human diseases. Adv Exp Med Biol. 2000;475:123–130.
  • Semenza GL. Targeting HIF-1 for cancer therapy.. Nature reviews. Cancer 2003;3(10): 721–732.
  • Quintero M, Mackenzie N, Brennan PA. Hypoxia-inducible factor 1 (HIF-1) in cancer. Eur J Surg Oncol. 2004;30(5):465–468.
  • Semenza GL. Development of novel therapeutic strategies that target HIF-1. Expert Opin Ther Targets. 2006;10(2):267–280.
  • Fallah J, Rini BI. HIF inhibitors: status of current clinical development. Curr Oncol Rep. 2019;21(1):6.
  • Hu C, Wang L, Chodosh LA, et al. Differential roles of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α in hypoxic gene regulation. Mol Cell Biol. 2003;23(24):9361–9374.
  • Loboda A, Jozkowicz A, Dulak JHIF. 1 versus HIF-2 - Is one more important than the other? Vascul Pharmacol. 2012;56(5):245–251.
  • Zhao J, Du F, Shen G, et al. The role of hypoxia-inducible factor-2 in digestive system cancers. Cell Death Dis. 2015;6(1):e1600–e1600.
  • Lee K, Won M, Ban HS, et al. inventors; univ dongguk ind acad coop and Korea Res inst bioscience and biotechnology, assignee. Hsp70 probe for detecting Hsp70 and manufacturing method thereof. Korea patent KR 101930131. 2016 Jun29.
  • Ban HS, Kim BK, Lee H, et al. The novel hypoxia-inducible factor-1α inhibitor IDF-11774 regulates cancer metabolism, thereby suppressing tumor growth. Cell Death Dis. 2017;8(6):e2843.
  • Ban HS, Naik R, Kim HM, et al. Identification of Targets of the HIF-1 Inhibitor IDF-11774 using alkyne-conjugated photoaffinity probes. Bioconjug Chem. 2016;27(8):1911–1920.
  • Suh Y, Lee S, Kim J, inventors; seoul national university, assignee. novel HIF-1α inhibitor, preparation method therefor, and pharmaceutical composition for preventing or treating angiogenesis-associated eye disease, containing same as active ingredient. World Organization patent WO 2020045856. 2020 Mar5.
  • Lee S, An H, Chang D-J, et al. Total synthesis of (−)-deguelin via an iterative pyran-ring formation strategy. Chem Commun. 2015;51(43):9026–9029.
  • Chang D, An H, Kim K, et al. Design, synthesis, and biological evaluation of novel deguelin-based heat shock protein 90 (HSP90) inhibitors targeting proliferation and angiogenesis. J Med Chem. 2012;55(24):10863–10884.
  • An H, Lee S, Lee JM, et al. Novel hypoxia-inducible factor 1α (HIF-1α) inhibitors for angiogenesis-related ocular diseases: discovery of a novel scaffold via ring-truncation strategy. J Med Chem. 2018;61(20):9266–9286.
  • Warfel NA, Dolloff NG, Dicker DT, et al. CDK1 stabilizes HIF-1α via direct phosphorylation of Ser668 to promote tumor growth. Cell Cycle. 2013;12(23):3689–3701.
  • Calderwood SK, Gong J. Heat shock proteins promote cancer: it’s a protection racket. Trends Biochem Sci. 2016;41(4):311–323.
  • Chen C, JIANG Z, WANG J, et al., inventors; macau univ of science and technology, assignee. method of isolating phenanthroindolizidine alkaloids from tylophora atrofolliculata with HIF-1 inhibitory activity, compositions comprising them and their use. Australian patent AU 2016100494. 2016 Jun9.
  • Hodges TW, Hossain CF, Kim Y, et al. Molecular-targeted antitumor agents: the saururus cernuus dineolignans manassantin B and 4-o-demethylmanassantin B are potent inhibitors of hypoxia-activated HIF-1. J Nat Prod. 2004;67(5):767–771.
  • Lee TH, Lee YM, Lee DH, inventors; kyungpook nat univ ind academic coop found, assignee. 1,2,3-triazolobenzopyran derivatives for anticancer agent. Korea patent KR 101836747. 2016 Dec 28.
  • Park K, Lee HE, Lee SH, et al. Molecular and functional evaluation of a novel HIF inhibitor, benzopyranyl 1,2,3-triazole compound. Oncotarget. 2017;8(5):7801–7813.
  • Wang B, Meir EV, Holmes JN, et al. inventors; georgia state university research foundation, emory university, assignee. benzhydrol derivatives for the management of conditions related to hypoxia inducible factors. World Organization patent WO 2016179108. 2016 Nov 10.
  • Gustafson KR, Schnermann MJ, Chan S, et al. inventors; united states department of health and human service, assignee. hypoxia-inducible factor 1 (HIF-1) inhibitors. World Organization patent WO 2016164412. 2016 Oct13.
  • Chan ST, Patel PR, Ransom TR, et al. Structural elucidation and synthesis of eudistidine a: an unusual polycyclic marine alkaloid that blocks interaction of the protein binding domains of p300 and HIF-1alpha. J Am Chem Soc. 2015;137(16):5569–5575.
  • Nakamura H, Minegishi H, inventors; Tokyo institute of technolog, assignee. benzopyrazole derivative. Japan patent JP 2016210687. 2016 Dec 15.
  • Minegishi H, Fukashiro S, Ban HS, et al. Discovery of indenopyrazoles as a new class of hypoxia inducible factor (HIF)-1 inhibitors. ACS Med Chem Lett. 2013;4(2):297–301.
  • Härter M, Beck H, Ellinghaus P, et al. inventors; bayer intellectual property GmbH, assignee. heterocyclically substituted aryl compounds as HIF inhibitors. European patent EP 2356113. 2015 Jan 7.
  • Qiao W, Bo Z, Jiayuan Z, et al. inventors; xiamen university, assignee. antitumor drug composition as well as application of reagent comprising iron ions. China patent CN 108721629. 2018 Nov 2.
  • Imenshahidi M, Hosseinzadeh H. Berberine and barberry (Berberis vulgaris): A clinical review. Phytother Res. 2019;33:504–523.
  • Bai L, Chen M, Jiang Z, et al. inventors; macau univ of science and technology, assignee. Berberine derivatives, their preparation and use. Australian patent AU 2017100179. 2017 Mar 30.
  • Liu Y, Wang YIN, inventors; children’s res inst children’s nat medical center, assignee. compositions and methods for treating graft versus host disease. World Organization patent WO 2017031341. 2016 Aug 18.
  • Liu Y, Wang YIN, Liu YAN, et al. inventors; children’s res inst children’s nat medical center, assignee. echinomycin formulation, method of making and method of use thereof. World Organization patent WO 2017083403. 2016 Nov 09.
  • Shoji JI, Katagiri K. Studies on quinoxaline antibiotics. II. New antibiotics, triostins A, B and C. J Antibiot. 1961;14:335–339.
  • Waring MJ, Wakelin LPG. Echinomycin: a bifunctional intercalating antibiotic. Nature. 1974;252(5485):653–657.
  • Gradishar WJ, Vogelzang NJ, Kilton LJ, et al. A phase II clinical trial of echinomycin in metastatic soft tissue sarcoma. Invest New Drugs. 1995;13(2):171–174.
  • Foster BJ, Clagett-Carr K, Shoemaker DD, et al. Echinomycin: the first bifunctional intercalating agent in clinical trials. Invest New Drugs. 1985;3(4):403–410.
  • Kong D, Park EJ, Stephen AG, et al. Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Res. 2005;65(19):9047–9055.
  • Bailey CM, Liu Y, Peng G. et al. Liposomal formulation of HIF-1α inhibitor Echinomycin eliminates established metastases of triple-negative breast Cancer. Nanomedicine. 2020; 102278.
  • Chung S, Jung D, Cho B, et al. inventors; Olipass Corp, assignee. HIF-1alpha antisense oligonucleotides. World Organization patent WO 2018069764. 2017 Oct11.
  • Disney M, inventor; scripps research inst, assignee. small molecule inhibition of micro-RNA-210 reprograms an oncogenic hypoxic circuit. World Organization patent WO 2018152414. 2018 Feb16.
  • Costales MG, Haga CL, Velagapudi SP, et al. Small molecule inhibition of microRNA-210 reprograms an oncogenic hypoxic circuit. J Am Chem Soc. 2017;139(9):3446–3455.
  • Li C, Li Q, Mei Q, et al. Pharmacological effects and pharmacokinetic properties of icariin, the major bioactive component in herba epimedii. Life Sci. 2015;126:57–68.
  • Asher G, Adamovich Tamam Y, Ladeuix B, inventors; Yeda Research and Development, assignee. Treatment of a circadian rhythm disorder. 2018Apr 26.
  • Jo H, Esmerats JF, Villa-Roel N, inventors; emory university, assignee. methods and compositions for managing vascular conditions using miR-483 mimics and HIF1alpha pathway inhibitors. United State patent US 20190112603. 2019 Apr18.
  • Fernandez Esmerats J, Villa-Roel N, Kumar S, et al. disturbed flow increases ube2c (ubiquitin e2 ligase c) via loss of miR-483-3p, inducing aortic valve calcification by the pvhl (von Hippel-lindau protein) and HIF-1α (hypoxia-inducible factor-1α) pathway in endothelial cells. Arterioscler Thromb Vasc Biol. 2019;39(3):467–481.
  • Lee K, Zhao Y, Kuo S, et al. inventors; china medical university, assignee. bicyclic compound and pharmaceutical composition thereof for treating stroke and use thereof patent. United States patent US 20170298049. 2017 Oct 19.
  • Yang M, Hsu DS, Wang H, et al. Bmi1 is essential in Twist1-induced epithelial–mesenchymal transition. Nat Cell Biol. 2010;12(10):982–992.
  • Chiu HY, Lee HT, Lee KH, et al. Mechanisms of ischaemic neural progenitor proliferation: a regulatory role of the HIF-1alpha-CBX7 pathway. Neuropathol Appl Neurobiol. 2020;46(4):391–405.
  • Levi B, Agarwal S, inventors; the regents of the university of michigan, assignee. method of treating heterotopic ossification. World Organization patent WO 2017112431. 2017 Jun 29.
  • Courtney KD, Infante JR, Lam ET, et al. Phase I dose-escalation trial of PT2385, a first-in-class hypoxia-inducible factor-2alpha antagonist in patients with previously treated advanced clear cell renal cell carcinoma. J Clin Oncol. 2018;36(9):867–874.
  • Yu Y, Yu Q, Zhang X. Allosteric inhibition of HIF-2alpha as a novel therapy for clear cell renal cell carcinoma. Drug Discov Today. 2019;24(12):2332–2340.
  • Wehn PM, Rizzi JP, Dixon DD, et al. 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.
  • Wallace EM, Rizzi JP, Han G, et al. A small-molecule antagonist of HIF2alpha Is efficacious in preclinical models of renal cell carcinoma. Cancer Res. 2016;76(18):5491–5500.
  • Xu R, Wang K, Rizzi JP, et al. 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.
  • Dixon Darryl D, Grina J, Josey John A, et al. inventors; Peloton Therapeutics Inc, assignee. Aromatic compounds and uses thereof. World Organization patent WO 2016144825. 2016 Sep 15.
  • Wehn P, Xu RUI, Yang H, inventors; Peloton Therapeutics Inc, assignee. Substituted pyridines and uses thereof. World Organization patent WO 2016144826. 2016 Sep 15.
  • Wehn P, Yang H, inventors; peloton therapeutics inc, assignee. tricyclic inhibitors of hif-2-alpha and uses thereof. United State patent US 20160362390. 2017 Oct24.
  • Josey John A, Wallace Eli M, Han G, inventors; peloton therapeutics inc, assignee. combination therapy of a hif-2-alpha inhibitor and an immunotherapeutic agent and uses thereof. World Organization patent WO 2016168510. 2016 Oct20.
  • Lindemann C, Stengel Peter J, inventors; peloton therapeutics inc, assignee. solid dispersions and pharmaceutical compositions comprising a substituted indane and methods for the preparation and use thereof. World Organization patent WO 2020092100. 2020 May 7.
  • Fu J, Lou Y, He Y, inventors; nikang therapeutics inc, assignee. 2,3-dihydrobenzo[b]thiophene derivatives as hypoxia inducible factor-2(alpha) inhibitors. World Organization patent WO 2020055883. 2020 Mar19.
  • Fu J, Lou Y, He Y, inventors; nikang therapeutics inc, assignee. Indane derivatives as hypoxia inducible factor-2(alpha) inhibitors. World Organization patent WO 2020081695. 2020 Apr23.
  • Matthias L, Buchstaller H-P, inventors; merck patent GMBH and Selvita S A, assignee. Thiophene derivatives. World Organization patent WO 2019219731. 2019 Nov 21.
  • Jin B, Dong Q, Hung G, inventors; Fronthera U S Pharmaceuticals Llc, assignee. Novel compounds, uses and methods for their preparation. World Organization patent WO 2018031680. 2018 Feb 15.
  • Tavassoli A, inventor; univ Southampton, assignee. HIF-1 and HIF-2 inhibitors. World Organization patent WO 2017129997. 2017 Aug3.
  • Josey John A, inventor; peloton therapeutics inc, assignee. Compositions for use in treating glioblastoma. World Organization patent WO 2016145045. 2016 Sep 15.
  • Kim MS, Brugarolas J, Hwang TH, et al. inventors; univ Texas, assignee. biomarkers of response to HIF-2-alpha inhibition in cancer and methods for the use thereof. World Organization patent WO 2017053192. 2017 Mar30.
  • Bruick RK, Chen Y, Ruiz JCF, inventors; univ Texas, assignee. HIF-2α inhibitors for treating iron overload disorders. World Organization patent WO 2016057242. 2016 Apr14.
  • Shah YM, Matsubara T, Ito S, et al. Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deficiency. Cell Metab. 2009;9(2):152–164.
  • Shah YM, Xie L. Hypoxia-inducible factors link iron homeostasis and erythropoiesis. Gastroenterology. 2014;146(3):630–642.
  • Josey JA, Shrimali R, Wallace EM, et al. inventors; peloton therapeutics inc, assignee. methods of reducing inflammation of the digestive system with inhibitors of hif-2-alpha. World Organization patent WO 2019191227. 2019 Oct3.
  • Chun T, Hikage F, inventors; univ michigan regents, assignee. compositions and methods for treating graves disease. World Organization patent WO 2019178329. 2019 Sep 19.
  • Hikage F, Atkins S, Kahana A, et al. HIF2A-LOX pathway promotes fibrotic tissue remodeling in thyroid-associated orbitopathy. Endocrinology. 2019;160(1):20–35.
  • Yin H, Xie L, Yin Amelia Y, inventors; univ of georgia research foundation inc, assignee. Compositions and methods for modulating HIF-2α to improve muscle generation and repair. World Organization patent WO 2019100053. 2019 May23.
  • Relaix F, Zammit PS. Satellite cells are essential for skeletal muscle regeneration: the cell on the edge returns centre stage. Development. 2012;139(16):2845–2856.
  • Xie L, Yin A, Nichenko AS, et al. Transient HIF2A inhibition promotes satellite cell proliferation and muscle regeneration. J Clin Investig. 2018;128(6):2339–2355.
  • Ban HS, Uto Y, Won M, et al. Hypoxia-inducible factor (HIF) inhibitors: a patent survey (2011-2015). Expert Opin Ther Pat. 2016;26(3):309–322.
  • Dixon DD, Grina J, Josey JA, et al. inventors; peloton therapeutics, inc., assignee. preparation of aryl ethers as HIF-2α inhibitors and use in treating cancer patent. World Organization patent WO 2015035223. 2015 Mar12.
  • Noman MZ, Hasmim M, Lequeux A, et al. Improving cancer immunotherapy by targeting the hypoxic tumor microenvironment: new opportunities and challenges. Cells. 2019;8(9):1083.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.