The immunomodulatory drugs (IMiDs) thalidomide, pomalidomide, and lenalidomide have been approved for the treatment of multiple myeloma for many years. Recently, their use as E3 ligase recruiting elements for small-molecule-induced protein degradation has led to a resurgence in interest in IMiD synthesis and functionalization. Traditional IMiD synthesis follows a stepwise route with multiple purification steps. Herein we describe a novel one-pot synthesis without purification that provides rapid access to a multitude of IMiD analogues. Binding studies with the IMiD target protein cereblon (CRBN) reveals a narrow structure-activity relationship with only a few compounds showing sub-micromolar binding affinity in the range of pomalidomide and lenalidomide. However, anti-proliferative activity as well as Aiolos degradation could be identified for two IMiD analogues. This study provides useful insight into the structure-degradation relationships for molecules of this type as well as a rapid and robust method for IMiD synthesis.
Keywords: cereblon; condensation reactions; imides; immunomodulatory drugs; protein degradation.
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.