Molecular Glues: Capable Protein-Binding Small Molecules That Can Change Protein–Protein Interactions and Interactomes for the Potential Treatment of Human Cancer and Neurodegenerative Diseases

Abstract

Molecular glue (MG) compounds are a type of unique small molecule that can change the protein–protein interactions (PPIs) and interactomes by degrading, stabilizing, or activating the target protein after their binging. These small-molecule MGs are gradually being recognized for their potential application in treating human diseases, including cancer. Evidence suggests that small-molecule MG compounds could essentially target any proteins, which play critical roles in human disease etiology, where many of these protein targets were previously considered undruggable. Intriguingly, most MG compounds with high efficacy for cancer treatment can glue on and control multiple key protein targets. On the other hand, a single key protein target can also be glued by multiple MG compounds with distinct chemical structures. The high flexibility of MG–protein interaction profiles provides rich soil for the growth and development of small-molecule MG compounds that can be used as molecular tools to assist in unraveling disease mechanisms, and they can also facilitate drug development for the treatment of human disease, especially human cancer. In this review, we elucidate this concept by using various types of small-molecule MG compounds and their corresponding protein targets that have been documented in the literature.

Binding of RAGE and RIPK1 induces cognitive deficits in chronic hyperglycemia‐derived neuroinflammation

“…Therefore, understanding and targeting protein–protein interactions are meaningful for the discovery of disease mechanisms and development of targeted drugs to treat disease. Small molecules that impede abnormal protein binding in disease states can have a therapeutic effect 46 . This is supported by our finding that mutation of RAGE AAs 362–367 prevents the interaction between RAGE and RIPK1, blocking activation of RIPK1 and its downstream inflammation‐related signaling pathway in db/db mice.…”

Template-assisted covalent modification of DCAF16 underlies activity of BRD4 molecular glue degraders

“…Molecular glue degraders have emerged as a powerful therapeutic modality, as demonstrated by the clinical successes of thalidomide analogs in the treatment of hematological malignancies 4,5 . These small molecule degraders stabilize the protein-protein interface between ubiquitin ligases and disease-relevant neosubstrates, resulting in ubiquitination and proteasomal degradation of the targets 6 . Unlike traditional occupancy-driven pharmacology of inhibitors, the event-driven pharmacology of degraders can result in more potent and sustained drug activity 7 .…”

“…The clinical efficacy of thalidomide derived drugs, such as lenalidomide, and the broad utility of targeted protein degradation in research and drug discovery has inspired numerous efforts to explore proximity-driven pharmacology 10-12 . While bi-functional molecules such as PROTACs can lead to rapid proof of concept and highly potent chemical probes, molecular glues are favorable for clinical development due to reduced size and overall chemical properties 6,9 . Despite these advantages, to date, only a small number of ubiquitin ligases have been exploited by molecular glue degraders, including CRBN 1,2 , DCAF15 13 and DDB1 14-16 .…”

“… Abstract Small molecules that induce protein-protein interactions to exert proximity-driven pharmacology such as targeted protein degradation are a powerful class of therapeutics 1-3 . Molecular glues are of particular interest given their favorable size and chemical properties and represent the only clinically approved degrader drugs 4-6 . The discovery and development of molecular glues for novel targets, however, remains challenging.…”

A Dissipative Supramolecular Glue for Temporal Control of Amplified Enzyme Activity and Biocatalytic Cascades

“…[15][16] Further, multiple weak non-covalent interactions such as electrostatics, hydrogen-bonding and van der Waals forces cause adhesion aiding in various biological processes such as the recruitment of white blood cells to inflamed tissue, 17 adherence of influenza virus, 18 and cell division. 19 Synthetic supramolecular systems featuring multivalent non-covalent interactions, termed "molecular glue", 20 provides an efficient scaffold for biomolecular adhesion 21 that have been useful to tailor various natural processes including protein-protein interactions, [22][23] protein-ligand interactions, 24 enzyme inhibition, [25][26][27] viral inhibition [28][29] and actomyosin sliding motion 21 in a site-selective manner. However, the utility of such molecular glues in the augmentation of the activity of biocatalytic cascades is non-existent.…”