Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure–Degradation Relationships

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.

De-Novo Design of Cereblon (CRBN) Effectors Guided by Natural Hydrolysis Products of Thalidomide Derivatives

“…Similar effects were observed in a recent study that was published during the preparation of this manuscript. 37 As both compounds, 4c and 4d , retained affinity to MsCI4, their overall binding mode is supposedly conserved and comparable to thalidomide, which is consistent with previous studies, showing that small modifications on the protruding moiety have little influence on the overall affinity to CRBN. 17,37 The binding modes of lenalidomide and pomalidomide have previously been reported to be virtually identical to thalidomide.…”

Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations

“…The CRBN-binding moieties of DGY-03-081 and DGY-04-035 were derived from lenalidomide and pomalidomide, respectively, two immunomodulatory imide drugs (IMiDs) that have been frequently deployed as CRBN binders 27 . DGY-08-097 was conjugated to a novel tricyclic imide moiety that has superior affinity for CRBN and does not induce degradation of IMiD neo-substrates such as IKZF1 and IKZF3 28 . All three compounds retain sub-micromolar IC 50 values for inhibition of HCV NS3/4A protease activity in a biochemical assay 29 (Fig.…”

Targeting oncoproteins with a positive selection assay for protein degraders

“…3B). We then repeated these experiments in 384-well plate format, exposing the cells to 10 different concentrations of a small library of approximately 100 analogs of POM that we had synthesized, which included the known IKZF1 degraders LEN, POM, and avadomide (MI-2-65) (11) and several uncharacterized IMiD-like molecules from the literature (12) (Fig. 3C and tables S1 and S2).…”