The nuclear export inhibitor aminoratjadone is a potent effector in extracellular-targeted drug conjugates

authored by

Philipp Klahn, Verena Fetz, Antje Ritter, Wera Collisi, Bettina Hinkelmann, Tatjana Arnold, Werner Tegge, Katharina Rox, Stephan Hüttel, Kathrin I. Mohr, Joachim Wink, Marc Stadler, Josef Wissing, Lothar Jänsch, Mark Brönstrup

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.

Organisation(s)

Centre of Biomolecular Drug Research (BMWZ)

External Organisation(s)

Helmholtz Centre for Infection Research (HZI)
Technische Universität Braunschweig
German Center for Infection Research (DZIF)

Type

Article

Journal

Chemical science

Volume

10

Pages

5197-5210

No. of pages

14

ISSN

2041-6520

Publication date

28.05.2019

Publication status

Published

Peer reviewed

Yes

ASJC Scopus subject areas

General Chemistry

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Electronic version(s)

https://doi.org/10.1039/c8sc05542d (Access: Open)