Aminopeptidase N: a multifunctional and promising target in medicinal chemistry
Status PubMed-not-MEDLINE Jazyk angličtina Země Velká Británie, Anglie Médium electronic-ecollection
Typ dokumentu časopisecké články, přehledy
PubMed
40703077
PubMed Central
PMC12285730
DOI
10.1039/d5ra03038b
PII: d5ra03038b
Knihovny.cz E-zdroje
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Aminopeptidase N (APN) is a zinc metalloproteinase present in almost all types of organisms and has various functions. Many of them are unrelated to its catalytic activity, which is why APN is sometimes classified as a moonlighting enzyme. APN is involved in carcinogenesis and angiogenesis. It also works as an entrance receptor for some coronaviruses and acts as a mediator during skin inflammation. Additionally, APN removes and helps to recycle regulatory proteins including neuropeptides, which is why its inhibitors hold therapeutic potential for a wide range of diseases, making the design and development of such molecules highly desirable. Some of them, such as bestatin or tosedostat, have already been tested as therapeutics with partial success. This article aims to bring an overview of multiple APN functions and implications for various diseases and their inhibitors which have already been prepared, and to suggest areas where the development of inhibitors may be promising in the future.
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Brenda:EC3.4.11.2 – Membrane Alanyl Aminopeptidase, https://www.brenda-enzymes.org/enzyme.php?ecno=3.4.11.2, assessed March 2025
Binkley F. Exp. Cell Res. 1952;2:145.
Binkley F. Alexander V. Bell F. E. Lea C. J. Biol. Chem. 1957;228:559. doi: 10.1016/S0021-9258(18)70641-8. PubMed DOI
Pfleiderer G., in Methods in Enzymology, Volume XIX Proteolytic Enzymes, ed. G. E. Perlman and L. Lorand, Academic Press, New York, 1st edn, 1970, Particle -Bound Aminopeptidase from Pig Kidney, pp. 514–521
Merck Sigma-Aldrich, https://www.sigmaaldrich.com/CZ/cs/substance/leucineaminopeptidasemicrosomalfromporcinekidney123459054631, assessed March 2025
Brenda:EC3.4.11.1 – Leucyl Aminopeptidase, https://www.brenda-enzymes.org/enzyme.php?ecno=3.4.11.1, assessed March 2025
Merops, https://www.ebi.ac.uk/merops/cgi-bin/famsum?family=M1, assessed March 2025
Favaloro E. J. Browning T. Facey D. Exp. Hematol. 1993;21:1695. PubMed
Wong A. H. Zhou D. Rini J. M. J. Biol. Chem. 2012;287:36804. doi: 10.1074/jbc.M112.398842. PubMed DOI PMC
Bosch B. J. Smits S. L. Haagmans B. L. Curr. Opin. Virol. 2014;6:55. doi: 10.1016/j.coviro.2014.03.011. PubMed DOI PMC
Luo H. Liang Z. Lin J. Wang Y. Liu Y. Mei K. Zhao M. Huang S. Front. Microbiol. 2024;15:1396894. doi: 10.3389/fmicb.2024.1396894. PubMed DOI PMC
Pasqualini R. Koivunen E. Kain R. Lahdenranta J. Sakamoto M. Stryhn A. Ashmun R. A. Shapiro L. H. Arap W. Ruoslahti E. Cancer Res. 2000;60:722. PubMed PMC
Mina-Osorio P. Trends Mol. Med. 2008;14:361. doi: 10.1016/j.molmed.2008.06.003. PubMed DOI PMC
Board P. G. Anders M. W. Drug Metab. Rev. 2021;53:76. doi: 10.1080/03602532.2020.1858857. PubMed DOI
KEGG, Glutathione Metabolism. Reference Pathway, https://www.kegg.jp/kegg-bin/show_pathway?map00480+3.4.11.2, assessed April 2025
Hanna P. E. Anders M. W. Crit. Rev. Toxicol. 2019;49:819. doi: 10.1080/10408444.2019.1692191. PubMed DOI
Fischer L. J. Green M. D. Harman A. W. Drug Metab. Dispos. 1985;13:121. doi: 10.1016/S0090-9556(25)08133-4. PubMed DOI
Giros B. Gros C. Solhonne B. Schwartz J. C. Mol. Pharmacol. 1986;29:281. doi: 10.1016/S0026-895X(25)10218-6. PubMed DOI
Miller B. C. Thiele D. L. Hersh L. B. Cottam G. L. Arch. Biochem. Biophys. 1994;311:174. doi: 10.1006/abbi.1994.1223. PubMed DOI
Lucius R. Sievers J. Mentlein R. J. Neurochem. 1995;64:1841. doi: 10.1046/j.1471-4159.1995.64041841.x. PubMed DOI
Wang L. H. Ahmad S. Benter I. F. Chow A. Mizutani S. Ward P. E. Peptides. 1991;12:1357. doi: 10.1016/0196-9781(91)90220-J. PubMed DOI
Drugbank, https://go.drugbank.com/drugs/DB00673, assessed April 2025
Xu Y. Wellner D. Scheinberg D. A. Biochem. Biophys. Res. Commun. 1995;208:664. doi: 10.1006/bbrc.1995.1390. PubMed DOI
Robertson M. J. Cunoosamy M. P. Clark K. L. Br. J. Pharmacol. 1992;106:166. doi: 10.1111/j.1476-5381.1992.tb14310.x. PubMed DOI PMC
Bodineau L. Frugière A. Marc Y. Claperon C. Llorens-Cortes C. Heart Failure Rev. 2008;13:311. doi: 10.1007/s10741-007-9077-3. PubMed DOI
Ward P. E. Benter I. F. Dick L. Wilk S. Biochem. Pharmacol. 1990;40:1725. doi: 10.1016/0006-2952(90)90348-O. PubMed DOI
Bauvois B. Dauzonne D. Med. Res. Rev. 2006;26:88. doi: 10.1002/med.20044. PubMed DOI PMC
P15144 AMPN_HUMANUniProt, Aminopeptidasae N, UniProt, https://www.uniprot.org/uniprotkb/P15144/entry, assessed June 2025
Dong X. An B. Salvucci Kierstead L. Storkus W. J. Amoscato A. A. Salter R. D. J. Immunol. 2000;164:129. doi: 10.4049/jimmunol.164.1.129. PubMed DOI
Lu C. Amin M. A. Fox D. A. J. Immunol. 2020;204:3. doi: 10.4049/jimmunol.1900868. PubMed DOI PMC
Villaseñor-Cardoso M. I. Frausto-Del-Río D. A. Ortega E. BioMed Res. Int. 2013;2013:562984. PubMed PMC
Morgan R. Endres J. Behbahani-Nejad N. Phillips K. Ruth J. H. Friday S. C. Edhayan G. Lanigan T. Urquhart A. Chung K. C. Fox D. A. Arthritis Rheumatol. 2015;67:74. doi: 10.1002/art.38878. PubMed DOI PMC
Zotz J. S. Wölbing F. Lassnig C. Kauffmann M. Schulte U. Kolb A. Whitelaw B. Müller M. Biedermann T. Huber M. FASEB J. 2016;30:2225. doi: 10.1096/fj.201600278. PubMed DOI
Bosch B. J. Smits S. L. Haagmans B. L. Curr. Opin. Virol. 2014;6:55. doi: 10.1016/j.coviro.2014.03.011. PubMed DOI PMC
Beyer D. K. Forero A. J. Mol. Biol. 2022;434:167265. doi: 10.1016/j.jmb.2021.167265. PubMed DOI PMC
Compton S. R. Comp. Med. 2021;71:333. doi: 10.30802/AALAS-CM-21-000007. PubMed DOI PMC
Tresnan D. B. Levis R. Holmes K. V. J. Virol. 1996;70:8669. doi: 10.1128/jvi.70.12.8669-8674.1996. PubMed DOI PMC
Söderberg C. Giugni T. D. Zaia J. A. Larsson S. Wahlberg J. M. Möller E. J. Virol. 1993;67:6576. doi: 10.1128/jvi.67.11.6576-6585.1993. PubMed DOI PMC
Gredmark S. Britt W. B. Xie X. Lindbom L. Söderberg-Nauclér C. J. Immunol. 2004;173:4897. doi: 10.4049/jimmunol.173.8.4897. PubMed DOI
Carl-McGrath S. Lendeckel U. Ebert M. Röcken C. Histol. Histopathol. 2006;21:1339. PubMed
Zhang Q. Wang J. Zhang H. Zhao D. Zhang Z. Zhang S. J. Cancer Res. Ther. 2015;11:223. doi: 10.4103/0973-1482.138007. PubMed DOI
Saida S. Watanabe K. Kato I. Fujino H. Umeda K. Okamoto S. Uemoto S. Hishiki T. Yoshida H. Tanaka S. Adachi S. Niwa A. Nakahata T. Heike T. Pediatr. Int. 2015;57:558. doi: 10.1111/ped.12597. PubMed DOI
Pang L. Zhang N. Xia Y. Wang D. Wang G. Meng X. Oncotarget. 2016;7:77854. doi: 10.18632/oncotarget.12835. PubMed DOI PMC
Liu Z. Yang Z. Xiong L. Li D. Zou Q. Yuan Y. Int. J. Clin. Oncol. 2020;25:1346. doi: 10.1007/s10147-020-01651-8. PubMed DOI
Fröhlich E. Engel E. Wahl R. Horm. Metab. Res. 2011;43:364. doi: 10.1055/s-0031-1273682. PubMed DOI PMC
Thielitz A. Reinhold D. Vetter R. Bank U. Helmuth M. Hartig R. Wrenger S. Wiswedel I. Lendeckel U. Kähne T. Neubert K. Faust J. Zouboulis C. C. Ansorge S. Gollnick H. J. Invest. Dermatol. 2007:1042. doi: 10.1038/sj.jid.5700439. PubMed DOI
Quesada A. Vargas F. Montoro-Molina S. O'Valle F. Rodríguez-Martínez M. D. Osuna A. Prieto I. Ramírez M. Wangensteen R. PLoS One. 2012;7:e40402. doi: 10.1371/journal.pone.0040402. PubMed DOI PMC
Muraoka S. Brodie W. D. Mattichak M. N. Gurrea-Rubio M. Ikari Y. Foster C. Amin M. A. Khanna N. Amin H. Campbell P. L. Vichaikul S. Model E. N. Omara M. M. Petrovski S. Kozicki K. Amarista C. Webber A. Ali M. Palisoc P. J. Hervoso J. Ruth J. H. Tsoi C. Varga J. Gudjonsson J. E. Khanna D. Fox D. A. Tsou P. S. Arthritis Rheumatol. 2025;77:80. doi: 10.1002/art.42973. PubMed DOI PMC
Li Z. Tomlinson A. C. A. Wong A. H. M. Zhou D. Desforges M. Talbot P. J. Benlekbir S. Rubinstein J. L. Rini J. M. eLife. 2019;8:e51230. doi: 10.7554/eLife.51230. PubMed DOI PMC
Doyle L. P. Hutchings L. M. J. Am. Vet. Med. Assoc. 1946;108:257. PubMed
Schwegmann-Wessels C. Herrler G. Dtsch. Tierarztl. Wochenschr. 2006;113:157. PubMed
Jung K. Saif L. J. Wang Q. Virus Res. 2020;286:1. doi: 10.1016/j.virusres.2020.198045. PubMed DOI PMC
Wang Q. Vlasova A. N. Kenney S. P. Saif L. J. Curr. Opin. Virol. 2019;34:39. doi: 10.1016/j.coviro.2018.12.001. PubMed DOI PMC
Song D. Park B. Virus Genes. 2012;44:167. doi: 10.1007/s11262-012-0713-1. PubMed DOI PMC
Boley P. A. Alhamo M. A. Lossie G. Yadav K. K. Vasquez-Lee M. Saif L. J. Kenney S. P. Emerging Infect. Dis. 2020;26:255. doi: 10.3201/eid2602.190346. PubMed DOI PMC
Mukhopadhyay S. Barnés C. M. Haskel A. Short S. M. Barnes K. R. Lippard S. J. Bioconjug. Chem. 2008;19:39. doi: 10.1021/bc070031k. PubMed DOI PMC
Zhang Z. Harada H. Tanabe K. Hatta H. Hiraoka M. Nishimoto S. Peptides. 2005;26:2182. doi: 10.1016/j.peptides.2005.03.049. PubMed DOI
Trencsényi G. Enyedi K. N. Mező G. Halmos G. Képes Z. Int. J. Mol. Sci. 2023;24:12675. doi: 10.3390/ijms241612675. PubMed DOI PMC
Shao Y. Liang W. Kang F. Yang W. Ma X. Li G. Zong S. Chen K. Wang J. Molecules. 2014;19:11600. doi: 10.3390/molecules190811600. PubMed DOI PMC
Li G. Wang X. Zong S. Wang J. Conti P. S. Chen K. Mol. Pharmaceutics. 2014;11:3938. doi: 10.1021/mp500354x. PubMed DOI
Kim D. W. Kim W. H. Kim M. H. Kim C. G. J. Labelled Compd. Radiopharm. 2015;58:30. doi: 10.1002/jlcr.3260. PubMed DOI
Dringen R. Gutterer J. M. Gros C. Hirrlinger J. J. Neurosci. Res. 2001;66:1003. doi: 10.1002/jnr.10042. PubMed DOI
Yang Y. Zhou J. Yu K. Amino Acids. 2014;46:449. doi: 10.1007/s00726-013-1638-2. PubMed DOI
P06756 ITAV_HUMAN, Integrin Alpha-V, UniProt, https://www.uniprot.org/uniprotkb/P06756/entry, assessed April 2025
Satraplatin for Patients with Metastatic Breast Cancer (MBC), National Library of Medicine, ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT00265655?intr=Satraplatin&page=1&rank=3, assessed March 2025
Luan Y. Jing F. Zhang J. Zou M. Wang X. Jia Y. Liu N. Mou J. Xu W. Protein Pept. Lett. 2012;19:1122. doi: 10.2174/092986612802762615. PubMed DOI
Enyedi K. N. Tóth S. Szakács G. Mező G. PLoS One. 2017;12:e0178632. doi: 10.1371/journal.pone.0178632. PubMed DOI PMC
Study of NGR-hTNF as Single Agent in Patients Affected by Advanced or Metastatic Malignant Pleural Mesothelioma (NGR010). National Library of Medicine, ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT00484276?locStr=Italy&country=Italy&cond=Malignant%20Pleural%20Mesothelioma&rank=15&page=2, assessed March 2025
DiNardo C. D. Cortes J. E. Expert Opin. Invest. Drugs. 2014;23:265. doi: 10.1517/13543784.2014.864276. PubMed DOI
Davenport E. Aronson L. I. Davies F. E. Autophagy. 2009;5:1052. doi: 10.4161/auto.5.7.9510. PubMed DOI
Du K. Grocott L. Anichini G. O'Neill K. Syed N. Biomedicines. 2024;12:2481. doi: 10.3390/biomedicines12112481. PubMed DOI PMC
Umezawa H. Aoyagi T. Suda H. Hamada M. Takeuchi T. J. Antibiot. 1976;29:97. doi: 10.7164/antibiotics.29.97. PubMed DOI
Suda H. Takita T. Aoyagi T. Umezawa H. J. Antibiot. 1976;29:100. doi: 10.7164/antibiotics.29.100. PubMed DOI
Zhao S. Yao K. Li D. Liu K. Jin G. Yan M. Wu Q. Chen H. Shin S. H. Bai R. Wang G. Bode A. M. Dong Z. Guo Z. Dong Z. EBioMedicine. 2019;44:361. doi: 10.1016/j.ebiom.2019.05.008. PubMed DOI PMC
European Medicinal Agency, EU/3/16/1638 – Orphan Designation for Treatment of Pulmonary Arterial Hypertension. Ubenimex, https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-16-1638, assessed April 2025
Sengupta S. Horowitz P. M. Karsten S. L. Jackson G. R. Geschwind D. H. Fu Y. Berry R. W. Binder L. I. Biochemistry. 2006;45:15111. doi: 10.1021/bi061830d. PubMed DOI
Yasumitsu T. Ohshima S. Nakano N. Kotake Y. Tominaga S. Acta Oncol. 1990;29:827. doi: 10.3109/02841869009093009. PubMed DOI
Ichinose Y. Genka K. Koike T. Kato H. Watanabe Y. Mori T. Iioka S. Sakuma A. Ohta M. J. Natl. Cancer Inst. 2003;95:605. doi: 10.1093/jnci/95.8.605. PubMed DOI
Niimoto M. Hattori T. Biomed. Pharmacother. 1991;45:121. doi: 10.1016/0753-3322(91)90132-D. PubMed DOI
Usuka Y. Saito Y. Biomed. Pharmacother. 1991;45:87. doi: 10.1016/0753-3322(91)90127-F. PubMed DOI
Bestatin, National Library of Medicine, ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT02700529?intr=bestatin&rank=4 assessed April 2025
Pharmaceuticals and Medical Devices Agency of Japan, Japanese Pharmacopoeia, 18
Scornik O. A. Botbol V. Curr. Drug Metab. 2001;2:67. doi: 10.2174/1389200013338748. PubMed DOI
Amastatin, National Library of Medicine, PubChem, https://pubchem.ncbi.nlm.nih.gov/compound/439518, assessed April 2025
Aoyagi T. Tobe H. Kojima F. Hamada M. Takeuchi T. Umezawa H. J. Antibiot. 1978;31:636. doi: 10.7164/antibiotics.31.636. PubMed DOI
Meisenberg G. Simmons W. H. Peptides. 1984;5:535. doi: 10.1016/0196-9781(84)90083-4. PubMed DOI
Gera L. Fortin J. P. Adam A. Stewart J. M. Marceau F. J. Pharmacol. Exp. Ther. 2006;317:300. doi: 10.1124/jpet.105.095661. PubMed DOI
Shibata M. Koike M. Kusumi S. Sato N. Uchiyama Y. A. Arch. Histol. Cytol. 2016;76:1. doi: 10.1679/aohc.76.1. DOI
Ganji R. J. Reddi R. Gumpena R. Marapaka A. K. Arya T. Sankoju P. Bhukya S. Addlagatta A. Protein Sci. 2014;24:823. doi: 10.1002/pro.2653. PubMed DOI PMC
Ragusa S. Mouchet P. Lazennec C. Dive V. Meinnel T. J. Mol. Biol. 1999;289:1445. doi: 10.1006/jmbi.1999.2832. PubMed DOI
Drugbank, Tosedostat, https://go.drugbank.com/drugs/DB11781, assessed April 2025
Tosedostat, National Library of Medicine, ClinicalTrials.gov, https://clinicaltrials.gov/search?intr=Tosedostat&page=1, assessed April 2025
Halcrow B. E. Kermack W. O. J. Chem. Soc. 1946:155. doi: 10.1039/JR9460000155. PubMed DOI
Brenda:EC3.4.11.20 – Aminopeptidase Ey, https://www.brenda-enzymes.org/enzyme.php?ecno=3.4.11.20#SYNONYM, assessed April 2025
Browne P. O'Cuinn G. Eur. J. Biochem. 1983;137:75. doi: 10.1111/j.1432-1033.1983.tb07797.x. PubMed DOI
Hara T. Matsuzaki H. Nakamura T. Yoshida E. Ohkubo T. Maruyama H. Yamamoto C. Saito S. Kaji T. Fundam. Toxicol. Sci. 2016;3:109. doi: 10.2131/fts.3.109. DOI
Levdanskii V. A. Levdanskii A. V. Kuznetsov B. N. Chem. Nat. Compd. 2015;51:894. doi: 10.1007/s10600-015-1442-1. DOI
Xu W. Li Q. Curr. Med. Chem.:Anti-Cancer Agents. 2005;5:281. doi: 10.2174/1568011053765949. PubMed DOI
Evaluation of 20% Betulinic Acid Ointment for Treatment of Dysplastic Nevi (Moderate to Severe Dysplasia), National Library of Medicine, ClinicalTrials.gov, https://clinicaltrials.gov/study/NCT00346502?cond=Dysplastic%20Nevus%20Syndrome&rank=1&tab=results#more-information, assessed April 2025
Eiznhamer D. A. Xu Z. Q. IDrugs. 2004;7:359. PubMed
Fernandes S. Vieira M. Prudêncio C. Ferraz R. Int. J. Mol. Sci. 2024;25:2108. doi: 10.3390/ijms25042108. PubMed DOI PMC
European Bioinformatics Institute, EMBL-EBI ID: CHEMBL1852660, https://www.ebi.ac.uk/chembl/explore/compound/CHEMBL1852660, assessed April 2025
Maiereanu C. Schmitt C. Schifano-Faux N. Le Nouën D. Defoin A. Tarnus C. Bioorg. Med. Chem. 2011;19:5716. doi: 10.1016/j.bmc.2011.06.089. PubMed DOI
Schmitt C. Voegelin M. Marin A. Schmitt M. Schegg F. Hénon P. Guenot D. Tarnus C. Bioorg. Med. Chem. 2013;21:2135. doi: 10.1016/j.bmc.2012.12.038. PubMed DOI
Oh K. B. Oh M. N. Kim J. G. Shin D. S. Shin J. Appl. Microbiol. Biotechnol. 2006;70:102. doi: 10.1007/s00253-005-0040-8. PubMed DOI
Shim J. S. Lee H.-S. Shin J. Kwon H. J. Cancer Lett. 2004;203:163. doi: 10.1016/j.canlet.2003.08.036. PubMed DOI
Ansorge S., Bank U., Lendeckel U., Tadje J., Taeger M. and Wolke C., IMTM GMBH, US Pat., 2011117069A1, 2011
Farsa O. Ballayová V. Žáčková R. Kollar P. Kauerová T. Zubáč P. Int. J. Mol. Sci. 2022;23:9813. doi: 10.3390/ijms23179813. PubMed DOI PMC
Iskander M. F. Mishrikey M. M. El-Sayed L. El-Toukhy A. J. Inorg. Nucl. Chem. 1979;41:815. doi: 10.1016/0022-1902(79)80272-9. DOI
Abou El-Reash G. M. Kenawy I. M. El-Ayaan U. I. Khattab M. A. Synth. React. Inorg. Met.-Org. Chem. 1994;24:813. doi: 10.1080/00945719408001303. DOI
Wester D. W. Palenik G. J. Inorg. Chem. 1978;17:864. doi: 10.1021/ic50182a014. DOI
Abboud K. A. Palenik R. C. Palenik G. J. Inorg. Chim. Acta. 2004;357:321. doi: 10.1016/S0020-1693(03)00438-9. DOI
Muleta F. Desalegn T. Eswaramoorthy R. Garg A. J. Mol. Struct. 2022;1268:133632. doi: 10.1016/j.molstruc.2022.133632. DOI
Turner A. J., in Handbook of Proteolytic Enzymes, ed. J. Barrett, N. D. Rawlings and J. F. Woessner, 2004, vol. 1, Membrane Alanyl Aminopeptidase, pp. 289–294
Krige D. Needham L. A. Bawden J. Flores N. Farmer H. Miles L. E. C. Stone E. Callaghan J. Chandler S. Clark V. L. Kirwin-Jones P. Legris V. Owen J. Patel T. Wood S. Box G. Laber D. Odedra R. Wright A. Wood L. M. Eccles S. A. Bone E. A. Ayscough A. Drummond A. H. Cancer Res. 2008;68:6669. doi: 10.1158/0008-5472.CAN-07-6627. PubMed DOI
Žáčková R., Master thesis, Masaryk University, 2022
Drinkwater N. Bamert R. S. Sivaraman K. K. Paiardini A. McGowan S. Proteins. 2015;83:789. doi: 10.1002/prot.24771. PubMed DOI
Salvesen G. S. and Nagase H., in Proteolytic Enzymes. A Practical Approach, ed. J. Benyon and J. S. Bond, 2001, vol. 2, Inhibition of Proteolytic Enzymes, pp. 105–130
Brenda: EC 3.3.2.6 – Leukotriene-A4 Hydrolase, https://www.brenda-enzymes.org/enzyme.php?ecno=3.3.2.6, assessed June 2025
ClinicalSup.jp, Bestatin Capsules, https://clinicalsup.jp/jpoc/DrugInfoPdf/00055373.pdf, assessed June 2025
DrugBank, Ubenimex, https://go.drugbank.com/drugs/DB03424, assessed June 2025
Zhou S. F. Zhou Z. W. Yang L. P. Cai J. P. Curr. Med. Chem. 2009;16:3480. doi: 10.2174/092986709789057635. PubMed DOI
Lkhagvaa B. Tani K. Sato K. Toyoda Y. Suzuka C. Sone T. Cytokine. 2008;44:386. doi: 10.1016/j.cyto.2008.10.011. PubMed DOI
Yamagishi H. Naito K. Ueda Y. Itoi S. Kohnosu H. Kobayashi M. Kubo H. Matsuda A. Oka T. Biomed. Pharmacother. 1991;45:117. doi: 10.1016/0753-3322(91)90131-C. PubMed DOI
Kim H. W. Ko M. K. Park S. H. Shin S. Kim S. M. Park J. H. Lee M. J. Vaccines. 2023;11:1690. doi: 10.3390/vaccines11111690. PubMed DOI PMC
Wang H. Zhang Q. Ma P. Huang N. Chen Y. Cheng Y. Chen J. J. Neurophysiol. 2025;133:1902. doi: 10.1152/jn.00381.2024. PubMed DOI
Rama Varma S. Elagha B. M. M. Narayanan J. K. Mathew A. Front. Dent. Med. 2025;6:1571989. doi: 10.3389/fdmed.2025.1571989. PubMed DOI PMC
Gao J. J. Gao Z. H. Zhao C. R. Yuan Y. Cui S. X. Zhang X. F. Cheng Y. N. Xu W. F. Tang W. Qu X. J. Invest. New Drugs. 2011;29:574. doi: 10.1007/s10637-010-9391-9. PubMed DOI
Verbrugge S. E. Al M. Assaraf Y. G. Kammerer S. Chandrupatla D. M. Honeywell R. Musters R. P. Giovannetti E. O'Toole T. Scheffer G. L. Krige D. de Gruijl T. D. Niessen H. W. Lems W. F. Kramer P. A. Scheper R. J. Cloos J. Ossenkoppele G. J. Peters G. J. Jansen G. Oncotarget. 2016;7:5240. doi: 10.18632/oncotarget.6169. PubMed DOI PMC
Jansen G. Al M. Assaraf Y. G. Kammerer S. van Meerloo J. OssenkoppeleJ G. J. Cloos J. Peters G. J. Cancer Drug Resist. 2023;6:430. doi: 10.20517/cdr.2023.20. PubMed DOI PMC
van Herpen C. M. Eskens F. A. de Jonge M. Desar I. Hooftman L. Bone E. A. Timmer-Bonte J. N. Verweij J. A. Br. J. Cancer. 2010;103:1362. doi: 10.1038/sj.bjc.6605917. PubMed DOI PMC
Mawad R. Becker P. S. Hendrie P. Scott B. Wood B. L. Dean C. Sandhu V. Deeg H. J. Walter R. Wang L. Myint H. Singer J. W. Estey E. Pagel J. M. Br. J. Haematol. 2016;172:238. doi: 10.1111/bjh.13829. PubMed DOI
Reid A. H. Protheroe A. Attard G. Hayward N. Vidal L. Spicer J. Shaw H. M. Bone E. A. Carter J. Hooftman L. Harris A. S J. De Bono Clin. Cancer Res. 2009;15:4978. doi: 10.1158/1078-0432.CCR-09-0306. PubMed DOI
European Medicinal Agency, EU/3/09/659 – Orphan Designation for Treatment of Acute Myeloid Leukaemia, Tosedostat, https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-09-659, assessed June 2025
Amin S. A. Adhikari N. Jha T. J. Med. Chem. 2018;61:6468. doi: 10.1021/acs.jmedchem.7b00782. PubMed DOI
Pal R. Singh K. Khan S. A. Chawla P. Kumar B. Akhtar M. J. Eur. J. Med. Chem. 2021;226:113890. doi: 10.1016/j.ejmech.2021.113890. PubMed DOI
Lipinski C. A. Lombardo F. Dominy B. W. Feeney P. J. Adv. Drug Delivery Rev. 1997;23:3. doi: 10.1016/S0169-409X(96)00423-1. PubMed DOI
Drugbank, Betulinic Acid. https://go.drugbank.com/drugs/DB12480, assessed June 2025
Schalk C. d'Orchymont H. Jauch M. F. Tarnus C. Arch. Biochem. Biophys. 1994;311:42. doi: 10.1006/abbi.1994.1206. PubMed DOI
119 Brenda: EC 3.5.1.98 – Histone Deacetylase, https://www.brenda-enzymes.org/enzyme.php?ecno=3.5.1.98, assessed June 2025
Pastorek J. Pastorekova S. Semin. Cancer Biol. 2015;31:52. doi: 10.1016/j.semcancer.2014.08.002. PubMed DOI
Gourin C. Alai S. Hantz S. Front. Microbiol. 2023;14:1321116. doi: 10.3389/fmicb.2023.1321116. PubMed DOI PMC
Shang Z. Li X. Mol. Biomed. 2024;5:61. doi: 10.1186/s43556-024-00226-7. PubMed DOI PMC
Fejzo J. Lepre C. A. Peng J. W. Bemis G. W. Ajay Murcko M. A. Moore J. M. Chem. Biol. 1999;6:755. doi: 10.1016/S1074-5521(00)80022-8. PubMed DOI