Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure–Degradation Relationships. (4th July 2018)

• Record Type: Journal Article
• Authors: Burslem, George M.; Ottis, Philipp; Jaime‐Figueroa, Saul; Morgan, Alicia; Cromm, Philipp M.; Toure, Momar; Crews, Craig M.
• Is Part Of: ChemMedChem. Volume 13:Number 15(2018)
• Page Start: 1508
• Page End: 1512
• Publication Date: 2018-07-04
• Subjects: cereblon -- condensation reactions -- imides -- immunomodulatory drugs -- protein degradation; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201800271
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: 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. Abstract : Targeted degradation : Herein we disclose a rapid and efficient synthesis of immunomodulatory drugs (IMiDs). This approach enabled the preparation of a wide variety of analogues with good functional group tolerance. Furthermore, we explored the binding of these analogues to the E3 ligase cereblon (CRBN) biophysically and characterized their cellular activity, revealing further details about the structure–degradation relationships for molecules of this type.