Clues to molecular glues

PROTACs: past, present and future

“…This should not drastically decrease the PROTACs affinity for its targets because the new PPI formed between the POI and E3 ligase can compensate for subtle losses of target affinity by the modified ligands. Using this strategy, researchers may be able to rationally re-design a PROTAC into a molecular glue, 146 which is currently more often discovered serendipitously rather than through a rational designed process. This proved feasible, to some extent, by Han et al in 2019 59 when they demonstrated that highly potent and efficient PROTAC degraders can be successfully obtained using an E3 ligase ligand with a micromolar binding affinity to the E3 ligase (Fig.…”

Chasing molecular glue degraders: screening approaches

“…1) are single linker-less molecules that induce the degradation of proteins by orchestrating (1) indirect E3:target dimerizations (destabilizers 34–36 – e.g. , fulvestrant) or (2) direct E3:target interactions (MG degraders 37–40 – e.g. , lenalidomide).…”

Molecular glues: The adhesive connecting targeted protein degradation to the clinic

“…60 As shown in Supplemental Information Table 1, dCeMM1 shares a similar arylsulfonamide structure and activity as other RBM39 degraders such as Indisulam, recruiting RBM39 to the DCAF15 subunit of CRL DCAF15 . 28 dCeMM 2/3/4 are cyclin K degraders that stabilize cyclin-dependent kinase 12 (CDK12)-cyclin K binding to DDB1CUL4B E3 at the CDK12-DDB1 interface. While dCeMM2/3 are structurally novel and similar to each other, dCeMM4 shares similarity with other cyclin K degraders such as Glue01 (Supplemental Information Table 1).…”

“…AUX/IAA and JAZ represent families of transcriptional repressors, which upon degradation lead to the expression of Auxin-and JAinducible genes. 28,120…”

“…In contrast to the original PROTACs, in which two ligands are connected by a flexible linker which can twist and turn and allow the two proteins to form contacts, molecular glues were believed to more directly enhance complex formation between an E3 ligase and a target protein by squeezing between protein-protein interfaces and are generally defined as small molecules that interact with two protein surfaces to induce or enhance affinity of these two proteins to each other (Figure 2). 28 The term "molecular glue" was initially coined to describe the mechanism of action of cyclosporin A and FK506 inducing novel protein-protein associations. 29 The molecular glue degraders such as thalidomide were discovered retrospectively, after their FDA approval and later detection of their immunomodulatory and anti-inflammatory activity.…”