1. Revisiting the antiangiogenic mechanisms of fluorinated thalidomide derivatives.
- Author
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Sievers J, Voget R, Lu F, Garchitorena KM, Ng YLD, Chau CH, Steinebach C, Figg WD, Krönke J, and Gütschow M
- Subjects
- Humans, Structure-Activity Relationship, Molecular Structure, Halogenation, Dose-Response Relationship, Drug, Human Umbilical Vein Endothelial Cells drug effects, Ubiquitin-Protein Ligases metabolism, Angiogenesis Inhibitors pharmacology, Angiogenesis Inhibitors chemistry, Angiogenesis Inhibitors chemical synthesis, Thalidomide pharmacology, Thalidomide chemistry, Thalidomide analogs & derivatives, Thalidomide chemical synthesis
- Abstract
Introduction of fluorine into bioactive molecules has attracted much attention in drug development. For example, tetrafluorination of the phthalimide moiety of immunomodulatory drugs (IMiDs) has a strong beneficial effect on the ability to inhibit angiogenesis. The neomorphic activity of E3 ligase complexes is induced by the binding of IMiDs to cereblon. We investigated that a set of eight thalidomide analogs, comprising non- and tetrafluorinated counterparts, did not induce the degradation of neomorphic substrates (IKZF3, GSPT1, CK1α, SALL4). Hence, the antiangiogenic activity of fluorinated IMiDs was not triggered by neosubstrate degradation features. A fluorine scanning of non-traditional IMiDs of the benzamido glutarimide chemotype was performed. By measuring the endothelial cell tube formation, no angiogenesis inhibitors were identified, confirming the narrow structure-activity window of IMiD-induced antiangiogenesis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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