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Cited by 60Hedgehog Signaling Pathway StudiesSynthesis and biological activitySynthesis and Characterization of Heterocyclic Compounds

Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic

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Pace, Jennifer R., DeBerardinis, Albert M., Sail, Vibhavari, Tacheva-Grigorova, Silvia K., Chan, Kelly A., Tran, Raymond, Raccuia, Daniel S., Wechsler-Reya, Robert J. +1 more·2016·Journal of Medicinal Chemistry
DOI 10.1021/acs.jmedchem.5b01718PMC PMC5061146
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Abstract

Itraconazole (ITZ) is an FDA-approved member of the triazole class of antifungal agents. Two recent drug repurposing screens identified ITZ as a promising anticancer chemotherapeutic that inhibits both the angiogenesis and hedgehog (Hh) signaling pathways. We have synthesized and evaluated first- and second-generation ITZ analogues for their anti-Hh and antiangiogenic activities to probe more fully the structural requirements for these anticancer properties. Our overall results suggest that the triazole functionality is required for ITZ-mediated inhibition of angiogenesis but that it is not essential for inhibition of Hh signaling. The synthesis and evaluation of stereochemically defined des-triazole ITZ analogues also provides key information as to the optimal configuration around the dioxolane ring of the ITZ scaffold. Finally, the results from our studies suggest that two distinct cellular mechanisms of action govern the anticancer properties of the ITZ scaffold.

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Crossref · 10.1021/acs.jmedchem.5b01718

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  • Preclinical investigations have verified that itraconazole can treat cancer by blocking the Hedgehog pathway.

    “Furthermore, a number of preclinical investigations have verified that ITZ can treat cancer by blocking the Hh pathway41,42 (Fig. 2).”

    From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [41]

    The Introduction identifies itraconazole as a Hedgehog-pathway inhibitor, and Results > Biological Evaluation reports inhibition of proliferation in Hedgehog-dependent murine medulloblastoma cells. These preclinical cell findings support its anticancer potential, but they do not verify that itraconazole can treat cancer by blocking that pathway. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Itraconazole suppresses the Hedgehog pathway by blocking SMO and/or GLI, particularly GLI1, and their downstream targets through a variety of mechanisms.

    “By blocking SMO and/or GLI, particularly GLI1, and their downstream targets through a variety of mechanisms, ITZ has been shown to suppress the Hh pathway.”

    From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [41]

    The Discussion and Conclusions section says preliminary evidence indicates that itraconazole inhibits Hedgehog signaling through SMO, and the Results report reduced GLI1 mRNA expression. It does not establish that itraconazole directly blocks GLI1 or its downstream targets, or that it suppresses the pathway through a variety of mechanisms. Page numbers are unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • A screening analysis for approved small molecule medicines revealed that itraconazole inhibited the Hedgehog pathway with an IC50 of 690 nM and angiogenesis with an IC50 of 160 nM.

    “A screening analysis for approved small molecule medicines revealed that ITZ inhibited the Hh pathway with an IC50 of 690 nM and angiogenesis with an IC50 of 160 nM.41”

    From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [41]

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Research works printed but not linked: 35

  1. [1]Kim J Tang JY Gong R Kim J Lee JJ Clemons KV Chong CR Chang KS Fereshteh M Gardner D Reya T Liu JO Epstein EH Stevens DA Beachy PA Itraconazole, a commonly used antifungal that inhibits hedgehog pathway activity and cancer growth Cancer Cell 2010 17 388 399 20385363 PMC4039177
  2. [2]Chong CR Xu J Lu J Bhat S Sullivan DJ Jr Liu JO Inhibition of Angiogenesis by the Antifungal Drug Itraconazole ACS Chem Biol 2007 2 263 270 17432820
  3. [3]Odds FC Brown AJP Gow NAR Antifungal agents: mechanisms of action Trends Microbiol 2003 11 272 279 12823944
  4. [5]Amayke D Jagani Z Dorsch M Unraveling the therapeutic potential of the hedgehog pathway in cancer Nat Med 2013 19 1410 1422 24202394
  5. [6]Link G Ahmadian A Persson A Undén AB Afink G Williams C Uhlén M Toftgård R Lundeberg J Pontén PATCHED and p53 gene alterations in sporadic and hereditary basal cell carcinoma Oncogene 2001 20 7770 7778 11753655
  6. [7]Reifenberger J Wolter M Knobbe CB Köhler Schönicke A Scharwächter C Kumar K Blaschke B Ruzicka T Reifenberger G Somatic mutations in the PTCH, SMOH, SUFUH, and TP53 genes in sporadic basal cell carcinoma Br J Dermatol 2005 152 43 51 15656799
  7. [8]Gibson P Tong Y Robinson G Thompson MC Currie DS Eden C Kranenburg TA Hogg T Poppleton H Martin J Finkelstein D Pounds S Weiss A Patay Z Scoggins M Ogg R Pei Y Yang ZJ Brun S Lee Y Zindy F Lindsey JC Taketo MM Boop FA Sanford RA Gajjar A Clifford SC Roussel MF McKinnon PJ Gutmann DH Ellison DW Wechsler-Reya R Gilbertson RJ Subtypes of medulloblastoma have distinct developmental origins Nature 2010 468 1095 1099 21150899 PMC3059767
  8. [9]Banerjee U Hadden MK Recent advances in the design of Hedgehog pathway inhibitors for the treatment of malignancies Expert Opin Drug Discov 2014 9 7 751 771 24850423
  9. [10]Sharpe HJ Wang W Hannoush RN de Sauvage FJ Regulation of the oncoprotein smoothened by small molecules Nat Chem Biol 2015 11 246 255 25785427
  10. [11]Shojaei F Anti-angiogenesis therapy in cancer: current challenges and future perspectives Cancer Lett 2012 320 130 137 22425960
  11. [12]Kerbel RS Tumor angiogenesis New Engl J Med 2008 358 2039 2049 18463380 PMC4542009
  12. [13]Wahl O Oswald M Tretzel L Herres E Arend J Efferth T Inhibition of tumor angiogenesis by antibodies, synthetic small molecules and natural products Curr Med Chem 2011 18 3136 3155 21671856
  13. [14]Yoo SY Kwon SN Angiogenesis and its therapeutic opportunities Mediators of Inflammation 2013 Article ID 127170 PMC3745966 23983401
  14. [17]Prentice AG Glasmacher A Making sense of itraconazole pharmacokinetics J Antimicrob Chemother 2005 Suppl. S1 i17 i22 16120630
  15. [18]Kumar S Shen J Burgess DJ Nano-amorphous spray dried powder to improve oral bioavailability of itraconazole J Control Release 2014 192 95 102 25009979
  16. [20]Odds FC Brown AJP Gow NAR Antifungal agents: mechanisms of action Trends in Micro 2003 11 272 279 12823944
  17. [21]Isoherranen N Kunze KL Allen KE Nelson WL Thummel KE Role of itraconazole metabolites in CYP3A4 inhibition Drug Metab Disp 2004 32 1121 1131 15242978
  18. [22]Ji H Zhang W Zhou Y Zhang M Zhu J Song Y Lü J Zhu J A three-dimensional model of lanosterol 14α-demethylase of Candida albicans and its interactions with azole antifungals J Med Chem 2000 43 2493 2505 10891108
  19. [23]Castro-Puyana M Crego AL Marina ML Separation and quantitation of the four stereoisomers of itraconazole in pharmaceutical formulations by electrokinetic chromatography Electrophoresis 2006 27 887 895 16411272
  20. [24]Shi W Nacev BA Aftab BT Head S Rudin CM Liu JO Itraconazole side chain analogues: Structure-activity relationship studies for inhibition of endothelial cell proliferation, vascular endothelial growth factor receptor 2 (VEGFR2) glycosylation, and hedgehog signaling J Med Chem 2011 54 7363 7374 21936514 PMC3307530
  21. [25]Shi W Nacev BA Bhat S Liu JO Impact of Absolute Stereochemistry on the Antiangiogenic and Antifungal Activities of Itraconazole ACS Med Chem Lett 2010 1 4 155 159 21892383 PMC3165044
  22. [26]Heeres J Backx LJJ Van Cutsem J Antimycotic Azoles. 7. Synthesis and Antifungal Properties of a Series of Novel Triazol-3-ones J Med Chem 1984 27 894 900 6330360
  23. [28]Banerjee U Ghosh M Hadden MK Evaluation of vitamin D3 A-ring analogues as hedgehog pathway inhibitors Bioorg Med Chem Lett 2012 22 1330 1334 22226657
  24. [30]So PL Langston AW Daniallinia N Hebert JL Fujimoto MA Khaimskiy Y Aszterbaum M Epstein EH Long-term establishment, characterization and manipulation of cell lines from mouse basal cell carcinoma tumors Exp Dermatol 2006 15 742 750 16881970
  25. [31]Tang JY Xiao TZ Oda Y Chang KS Shpall E Wu A So PL Hebert J Bikle D Epstein EH Vitamin D3 inhibits hedgehog signaling and proliferation in murine basal cell carcinomas Cancer Prev Res 2011 4 744 751 PMC3088781 21436386
  26. [32]Yang ZJ Ellis T Markant SL Read TA Kessler JD Bourboulas M Schüller U Machold R Fishell G Rowitch DH Wainwright BJ Wechsler-Reya RJ Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells Cancer Cell 2008 14 135 145 18691548 PMC2538687
  27. [33]Markant SL Esparza LA Sun J Barton KL McCoig LM Grant GA Crawford JR Levy ML Northcott PA Shih D Remke M Taylor MD Wechsler-Reya RJ Targeting sonic hedgehog-associated medulloblastoma through inhibition of Aurora and Polo-like kinases Cancer Res 2013 73 6310 6322 24067506 PMC3800039
  28. [34]Brun SN Markant SL Esparza LA Garcia G Terry D Huang JM Pavlyukov MS Li XN Grant GA Crawford JR Levy ML Conway EM Smith LH Nakano I Berezov A Greene MI Wang Q Wechsler-Reya RJ Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma Oncogene 2015 34 3770 3779 25241898 PMC4369477
  29. [36]Yauch RL Dijkgraaf GJ Alicke B Januario T Ahn CP Holcomb T Pujara K Stinson J Callahan CA Tang T Bazan JF Kan Z Seshagiiri S Hann CL Gould SE Low JA Rudin CM de Sauvage FJ Smoothened mutation confers resistance to a hedgehog pathway inhibitor in medulloblastoma Science 2009 326 572 574 19726788 PMC5310713
  30. [37]Dijkgraaf GJP Alicke B Weinmann L Januario T West K Modrusan Z Burdick D Goldsmith R Robarge K Sutherlin D Scales SJ Gould SE Yauch RL de Sauvage FJ Small molecule inhibition of GDC-0449 refractory smoothened mutants and downstream mechanisms of drug resistance Cancer Res 2011 71 435 444 21123452
  31. [38]Pricl S Cartelazzi B Col VD Marson D Laurini E Fermeglia M Licitra L Pilotti S Bossi P Perrone F Smoothened (SMO) receptor mutations dictate resistance to vismodegib in basal cell carcinoma Mol Oncol 2015 9 389 397 25306392 PMC5528667
  32. [39]Sharpe HJ Pau G Dijkgraaf GJ Basses-Seguin N Modrusan Z Januario T Tsui V Durham AB Dlugosz AA Haverty PM Bourgon R Tang JY Sarin KY Dirix L Fisher DC Rudin CM Sofen H Migden MR Yauch RL de Sauvage FJ Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma Cancer Cell 2015 27 327 341 25759019 PMC5675004
  33. [40]Atwood SX Sarin KY Whitson RJ Li JR Kim G Rezaee M Ally MS Kim J Yao C Chang ALS Oro AE Tang JY Smoothened variants explain the majority of drug resistance in basal cell carcinoma Cancer Cell 2015 27 342 353 25759020 PMC4357167
  34. [41]Kim J Aftab BT Tang JY Kim D Lee AH Rezaee M Kim J Chen B King EM Borodovsky A Riggins GJ Epstein EH Beachy PA Rudin CM Itraconazole and arsenic trioxide inhibit hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists Cancer Cell 2013 23 23 34 23291299 PMC3548977
  35. [42]Maschinot CA Pace JR Hadden MK Small molecule synthetic inhibitors of Hh signaling as anti-cancer chemotherapeutics Curr Med Chem 2015 PMC5062741 26310919

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Authors
Pace, J. R., DeBerardinis, A. M., Sail, V., Tacheva-Grigorova, S. K., Chan, K. A., Tran, R., Raccuia, D. S., Wechsler-Reya, R. J., & Hadden, M. K.
Affiliations
  • University of Connecticut (US)
  • Sanford Burnham Prebys Medical Discovery Institute (US)
  • Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 2880 Torrey Pines Scenic Drive, La Jolla, California 92037, United States
Corresponding author
Hadden, M. Kyle
ORCID
Venue
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Published
2016-04-06
Volume
59
Issue
8
Pages
3635-3649
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
DOI
10.1021/acs.jmedchem.5b01718
PMC
PMC5061146
OpenAlex
W2336358768
Cited by
60
References
3
Citations by year
2026: 5 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 6 · 2021: 6 · 2020: 6 · 2019: 10 · 2018: 13 · 2017: 7
FWCI
5.20
Type
journal article
Language
en
Open access
Locations
  • Journal of Medicinal Chemistry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Cancer Institute (CA190617)
  • Research Foundation, University of Connecticut
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
  • Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
  • Physical Sciences › Chemistry › Organic Chemistry › Synthesis and Characterization of Heterocyclic Compounds
Keywords
itraconazole, drug repurposing, anticancer agents, angiogenesis inhibition, Hedgehog signaling, triazoles, structure-activity relationship, antifungal agents
MeSH terms
Zinc Finger Protein GLI1, Animals, Antifungal Agents, Antineoplastic Agents, Cell Line, Mice, Inbred C3H, RNA, Messenger, Itraconazole, Inhibitory Concentration 50, Mice

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