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.
Highlights
Extracellular-targeted drug conjugates (EDCs) have recently evolved into an innovative, clinically proven molecular format in tumor therapies.[1,2,3,4,5,6,7,8,9,10,11] The linkage of potent cytotoxins to appropriate carrier molecules, ligands with a high affinity forEdge Article and mediate its uptake via endocytosis.[31]
The results demonstrate that nuclear export inhibition is a promising mode-of-action for extracellular-targeted drug conjugate payloads
We report the synthesis of novel folate- and luteinizing hormone releasing hormone (LHRH)-based carrier molecules, their conjugation with aminoratjadone-payloads and their biological evaluation, which led to the discovery of novel EDCs with an antiproliferative activity in the low double-digit nanomolar range
Summary
Extracellular-targeted drug conjugates (EDCs) have recently evolved into an innovative, clinically proven molecular format in tumor therapies.[1,2,3,4,5,6,7,8,9,10,11] The linkage of potent cytotoxins to appropriate carrier molecules, ligands with a high affinity forEdge Article and mediate its uptake via endocytosis.[31]. Early clinical trials with the CRM1-inhibitor leptomycin B as a standalone drug failed due to its high systemic toxicity.[62]
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