The nuclear export inhibitor aminoratjadone is a potent effector in extracellular-targeted drug conjugates.
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Authors
Klahn, PhilippFetz, Verena
Ritter, Antje
Collisi, Wera
Hinkelmann, Bettina
Arnold, Tatjana
Tegge, Werner

Rox, Katharina
Hüttel, Stephan
Mohr, Kathrin I
Wink, Joachim

Stadler, Marc

Wissing, Josef
Jänsch, Lothar

Brönstrup, Mark

Issue Date
2019-05-28
Metadata
Show full item recordAbstract
The concept of targeted drug conjugates has been successfully translated to clinical practice in oncology. Whereas the majority of cytotoxic effectors in drug conjugates are directed against either DNA or tubulin, our study aimed to validate nuclear export inhibition as a novel effector principle in drug conjugates. For this purpose, a semisynthetic route starting from the natural product ratjadone A, a potent nuclear export inhibitor, has been developed. The biological evaluation of ratjadones functionalized at the 16-position revealed that oxo- and amino-analogues had very high potencies against cancer cell lines (e.g. 16R-aminoratjadone 16 with IC50 = 260 pM against MCF-7 cells, or 19-oxoratjadone 14 with IC50 = 100 pM against A-549 cells). Mechanistically, the conjugates retained a nuclear export inhibitory activity through binding CRM1. To demonstrate a proof-of-principle for cellular targeting, folate- and luteinizing hormone releasing hormone (LHRH)-based carrier molecules were synthesized and coupled to aminoratjadones as well as fluorescein for cellular efficacy and imaging studies, respectively. The Trojan-Horse conjugates selectively addressed receptor-positive cell lines and were highly potent inhibitors of their proliferation. For example, the folate conjugate FA-7-Val-Cit-pABA-16R-aminoratjadone had an IC50 of 34.3 nM, and the LHRH conjugate d-Orn-Gose-Val-Cit-pABA-16R-aminoratjadone had an IC50 of 12.8 nM. The results demonstrate that nuclear export inhibition is a promising mode-of-action for extracellular-targeted drug conjugate payloads.Citation
Chem Sci. 2019 Apr 15;10(20):5197-5210. doi: 10.1039/c8sc05542d. eCollection 2019 May 28.Affiliation
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.Publisher
Royal Society of ChemistryJournal
Chemical SciencePubMed ID
31191875Type
ArticleLanguage
enISSN
2041-6520ae974a485f413a2113503eed53cd6c53
10.1039/c8sc05542d
Scopus Count
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