A Versatile and Sustainable Multicomponent Platform for the Synthesis of Protein Degraders: Proof-of-Concept Application to BRD4-Degrading PROTACs

Abstract

The use of small molecules to induce targeted protein degradation is increasingly growing in the drug discovery landscape, and protein degraders have progressed rapidly through the pipelines. Despite the advances made so far, their synthesis still represents a significant burden and new approaches are highly demanded. Herein we report an unprecedented platform that leverages the modular nature of both multicomponent reactions and degraders to enable the preparation of highly decorated PROTACs. As a proof of principle, our platform has been applied to the preparation of potential BRD4-degrading PROTACs, resulting in the discovery of a set of degraders endowed with high degradation efficiency. Compared to the existing methods, our approach offers a versatile and cost-effective means to access libraries of protein degraders and increase the chance of identifying successful candidates.

Accessing three-branched high-affinity cereblon ligands for molecular glue and protein degrader design

“…So far, MCRs have attracted little attention in the field of E3 ligase ligand discovery and optimization. 39,40 With the aid of the Petasis reaction, easy access to three-winged substances with excellent CRBN binding affinities was realized. Their effects on neosubstrates, such as IKZF3, seem to be highly correlated with the affinity data.…”

Advancing Strategies for Proteolysis-Targeting Chimera Design

“…Current strategies for increasing synthetic throughput have been introduced through Staudinger ligation chemistry, 80 solid-phase synthesis, 81 copper-catalyzed click chemistry, 82 activated esters, 83 the rapid synthesis of PROTACs (Rapid-TAC) platform, 84 and the modular synthetic platform. 85 Notably, a late-stage single-step reductive deoxyge-nation method allows immediate conversion from thalidomidecontaining PROTACs to lenalidomide groups without a de novo synthesis. 86 A few studies have focused on the synthesis methodology of PROTAC fragments.…”

Accelerating Drug Discovery: Synthesis of Complex Chemotypes via Multicomponent Reactions

“…As a result, an ortho,ortho′-disubstituted aromatic ring directly attached to the ester moiety provided hydrolytic stability independent of the chemical nature of the R 2 group of the aldehyde (Scheme 2). However, when R 2 was a bulky substituent, an increased hydrolytic stability was observed only Recently, Pirali and colleagues 24 reported a cutting-edge application of MCRs to new chemical modalities, in particular to proteolysis targeting chimeras (PROTACs). 3 They leverage the versatility of the Passerini MCR as a modular synthetic platform to build heterobifunctional protein degraders.…”

“…Recently, Pirali and colleagues reported a cutting-edge application of MCRs to new chemical modalities, in particular to proteolysis targeting chimeras (PROTACs) . They leverage the versatility of the Passerini MCR as a modular synthetic platform to build hetero­bifunctional protein degraders.…”