On the correlation of cereblon binding, fluorination and antiangiogenic properties of immunomodulatory drugs

Christopher Heim, Samuel Maiwald, Christian Steinebach, Matthew K. Collins, Jonathan Strope, Cindy H. Chau, William D. Figg, Michael Gütschow, Marcus D. Hartmann*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Cereblon (CRBN), the substrate receptor of an E3 ubiquitin ligase complex, is a target of thalidomide and thalidomide-derived immunomodulatory drugs (IMiDs). The binding of these IMiDs to CRBN alters the substrate specificity of the ligase, thereby mediating multiple effects that are exploited in cancer therapy. However, to date, it is not clear which other possible targets might be involved in the efficacy of IMiDs. One especially prominent effect of a number of thalidomide analogs is their ability to inhibit angiogenesis, which is typically enhanced in fluorinated analogs. So far, the involvement of CRBN in antiangiogenic effects is under debate. Here, starting from a systematic set of thalidomide analogs and employing a quantitative in vitro CRBN-binding assay, we study the correlation of fluorination, CRBN binding and antiangiogenic effects. We clearly identify fluorination to correlate both with CRBN binding affinity and with antiangiogenic effects, but do not find a correlation between the latter two phenomena, indicating that the main target for the antiangiogenic effects of thalidomide analogs still remains to be identified.

Original languageEnglish
Pages (from-to)67-72
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume534
DOIs
StatePublished - 1 Jan 2021
Externally publishedYes

Keywords

  • CRBN
  • Cancer therapy
  • IMiDs
  • MST
  • Microscale thermophoresis

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