Antiangiogenic Activity and in Silico Cereblon Binding Analysis of Novel Thalidomide Analogs.

Megan L Peach,Michael Gütschow,Shaunna L Beedie,Marc C Nicklaus,Cindy H Chau,Neil Vargesson,Weiming Luo,David Tweedie,Matthew K Collins,Suzana Markolovic,Christian Steinebach,Nigel H Greig,William D Figg

doi:10.3390/molecules25235683

Abstract

Due to its antiangiogenic and anti-immunomodulatory activity, thalidomide continues to be of clinical interest despite its teratogenic actions, and efforts to synthesize safer, clinically active thalidomide analogs are continually underway. In this study, a cohort of 27 chemically diverse thalidomide analogs was evaluated for antiangiogenic activity in an ex vivo rat aorta ring assay. The protein cereblon has been identified as the target for thalidomide, and in silico pharmacophore analysis and molecular docking with a crystal structure of human cereblon were used to investigate the cereblon binding abilities of the thalidomide analogs. The results suggest that not all antiangiogenic thalidomide analogs can bind cereblon, and multiple targets and mechanisms of action may be involved.

Highlights

Despite its teratogenic toxicity, the antiangiogenic and anti-immunoinflammatory efficacy of thalidomide and its analogs have expanded its clinical use in the treatment of Hansen’s disease as well as multiple myeloma and other cancers [1,2,3]
To develop a model predictive of antiangiogenic activity, these analogs were screened in an ex vivo angiogenesis model, the rat aorta ring (RAR) assay
We previously demonstrated the RAR assay to be an accurate assessment of antiangiogenic activity, with cytotoxicity having no effect on microvessel outgrowth [27]

Summary

Introduction

The antiangiogenic and anti-immunoinflammatory efficacy of thalidomide and its analogs have expanded its clinical use in the treatment of Hansen’s disease as well as multiple myeloma and other cancers [1,2,3]. There are intense efforts to improve the potency of thalidomide while decreasing its toxicity. Thalidomide was originally believed to be a multitarget drug due to its wide range of biological effects, including reduced TNF-α production, decreased or destabilized COX-2 expression, downregulation of VEGF and FGF, NF-κB inhibition (possibly by suppression of IκB kinase), inhibition of prostaglandin E2 secretion, and α1-acid glycoprotein binding [4,5]. Molecules 2020, 25, 5683 of thalidomide and its analogs is that binding to cereblon itself induces all downstream effects by triggering the ubiquitin-dependent proteasomal degradation of substrates for the E3 complex [7,8,9].

Methods

Results

Conclusion