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

doi:10.1016/j.bbrc.2020.11.117

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.

Highlights

Thalidomide and its derivatives constitute the class of immunomodulatory drugs (IMiDs)
Thalidomide consists of a glutarimide and a phthalimide ring, which were both subject of a plethora of variations and substitutions in various studies focusing on the design and biological evaluation of analogs [4,5,6,7,8,9]
We employed a set of compounds based on 2phthalimidinoglutarimide and 2-benzamidoglutarimide (Gu3408, scaffold B) (Figure 1)

Summary

Introduction

Thalidomide and its derivatives constitute the class of immunomodulatory drugs (IMiDs). These have proven to be effective in diverse clinical settings, most prominently in cancer therapy [1,2]. The structural basis for the binding of thalidomide analogs to CRBN is well understood [20,21,22,23] and exploited in the development of degraders targeting CRBN [24,25,26] as well as applied in a variety of PROTACs for the selective degradation of a multitude of protein targets [27,28,29,30]. The relevance of CRBN for the antiangiogenic properties of thalidomide derivatives is currently under debate [31]

Methods

Results

Conclusion