Details
| Original language | English |
|---|---|
| Pages (from-to) | 5197-5210 |
| Number of pages | 14 |
| Journal | Chemical science |
| Volume | 10 |
| Issue number | 20 |
| Early online date | 15 Apr 2019 |
| Publication status | Published - 28 May 2019 |
Abstract
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.
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In: Chemical science, Vol. 10, No. 20, 28.05.2019, p. 5197-5210.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - The nuclear export inhibitor aminoratjadone is a potent effector in extracellular-targeted drug conjugates
AU - Klahn, Philipp
AU - Fetz, Verena
AU - Ritter, Antje
AU - Collisi, Wera
AU - Hinkelmann, Bettina
AU - Arnold, Tatjana
AU - Tegge, Werner
AU - Rox, Katharina
AU - Hüttel, Stephan
AU - Mohr, Kathrin I.
AU - Wink, Joachim
AU - Stadler, Marc
AU - Wissing, Josef
AU - Jänsch, Lothar
AU - Brönstrup, Mark
N1 - Funding Information: P. K. thanks the Alexander-von-Humboldt Foundation for a Feodor-Lynen Fellowship. The authors thank Janine Schreiber and Brigitte Kornak for experimental support and Ulrike Beu-tling, Heike Overwin and Christel Kakoschke for analytical support. The authors thank Dr Raimo Franke, Dr Giambattista Testolin and Dr Kevin Ferreira for helpful discussions.
PY - 2019/5/28
Y1 - 2019/5/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85066086001&partnerID=8YFLogxK
U2 - 10.1039/c8sc05542d
DO - 10.1039/c8sc05542d
M3 - Article
AN - SCOPUS:85066086001
VL - 10
SP - 5197
EP - 5210
JO - Chemical science
JF - Chemical science
SN - 2041-6520
IS - 20
ER -