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Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure–Degradation Relationships
Author(s) -
Burslem George M.,
Ottis Philipp,
JaimeFigueroa Saul,
Morgan Alicia,
Cromm Philipp M.,
Toure Momar,
Crews Craig M.
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800271
Subject(s) - pomalidomide , cereblon , chemistry , lenalidomide , thalidomide , combinatorial chemistry , small molecule , multiple myeloma , computational biology , ubiquitin ligase , stereochemistry , ubiquitin , biochemistry , biology , immunology , gene
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.