What is Molecular Glue?
Molecular glue is a kind of small chemical molecules that act on the interface between protein and protein. It is a branch of many targeted protein degradation technologies with better medicinal properties, but it is also a difficult one. Molecular glue recognizes and degrades Neo-substrate by modifying the surface of ubiquitin ligase. For example, sulfonamides antineoplastic drug Indisulam, immunomodulatory drugs Thalidomide and Lenalidomide.
Basic Structural Features of Molecular Glues
Small Molecule Compounds: Molecular glues are small molecules with simple chemical structures and a molecular weight generally less than 500 Da. They exhibit good cell permeability and can easily cross cell membranes to exert their effects intracellularly.
Dual Binding Capability: Molecular glues typically have the ability to bind both E3 ubiquitin ligases and target proteins, thereby facilitating interactions between the two.
Common Structural Types of Molecular Glues
- Organic Small Molecule Drugs: The examples of small molecule drugs in this category are thalidomide and its derivatives lenalidomide and pomalidomide. These compounds serve as immunomodulatory agents that attach themselves to CRBN protein within the CRL4CRBN E3 ligase complex leading to the degradation of specific transcription factors including IKZF1 and IKZF3. Thalidomide's structure includes imide functional groups that bind CRBN to trigger the degradation of target proteins.
- Natural Products: Molecular glue activity in natural products includes agents such as cyclosporin A and rapamycin. The immune response inhibition happens when cyclosporin A binds with both cyclophilin and calcineurin to form a ternary complex. Rapamycin interacts with FKBP12 and mTOR to create a ternary complex which blocks mTOR signaling.
Structure-Function Relationships of Molecular Glues
Binding Sites and Interactions: The structural features of molecular glue binding sites on E3 ligases and target proteins determine binding specificity and affinity. For instance, in the case of thalidomide binding to CRBN, residues such as His380, Trp382, and Trp388 in the thalidomide-binding domain (TBD) of CRBN are essential for interaction. Thalidomide binds to these residues, altering the conformation of CRBN and enabling it to recognize and bind to new target proteins.
Role of Chemical Groups: Certain chemical groups within molecular glues are crucial for inducing protein-protein interactions and target degradation. For example, the pyridine ring in lenalidomide contributes to binding with CRBN and affects the mode and stability of its interaction with the target protein.
Mechanism of Action of Molecular Glues
Degradation via the Ubiquitin-Proteasome Pathway: Molecular glues act as monovalent small molecules that bind to and alter the surface of E3 ubiquitin ligases. By doing so, they block the ligase's interaction with its natural substrates and induce the recruitment of specific target proteins for degradation. This facilitates the ubiquitination of the target proteins and ultimately leads to their degradation by the proteasome.
Non-Degradative Functions: Beyond inducing protein degradation, molecular glues can also modulate protein-protein interaction interfaces to enhance or stabilize otherwise weak interactions. This allows them to fine-tune the concentration or activity of specific intracellular proteins, acting like molecular "tuners" to precisely regulate protein interaction networks and influence signaling pathways within the cell.
Characteristics of Molecular Glues
Targeting 'Undruggable' Proteins: Many disease-related proteins are considered 'undruggable' by traditional approaches due to their complex biological features—such as having multiple domains or functional sites—which make stable binding with small molecules difficult. Molecular glues offer a potential solution by acting on targets that lack conventional small-molecule binding pockets, such as IKZF1/3.
Low Molecular Weight and Good Drug-Likeness: Molecular glues typically have a molecular weight below 500 Da, exhibit favorable chemical properties, and cause minimal steric hindrance. This leads to improved bioavailability. Compared to large and complex PROTAC molecules, molecular glues are more likely to meet Lipinski's Rule of Five, more easily penetrate cell membranes, support oral administration, and more readily cross the blood-brain barrier—making them promising candidates for treating central nervous system (CNS) diseases with high unmet clinical needs.
Molecular Glues vs PROTACs
Structural Differences: PROTACs are bifunctional molecules composed of three parts: a ligand for the target protein, a linker, and a ligand for an E3 ubiquitin ligase. In contrast, molecular glues are monovalent small molecules with relatively simpler structures.
Mechanism of Action: PROTACs bind to both the target protein and the E3 ubiquitin ligase via their respective ligands, forming a ternary complex that brings the target protein into proximity with the ligase, leading to its ubiquitination and subsequent degradation. Molecular glues, on the other hand, function by altering the surface characteristics of the E3 ligase or the target protein to enhance their interaction, thereby facilitating the ubiquitination and degradation of the target protein.
Pharmacological Properties: Molecular glues are smaller in molecular weight and are expected to possess better pharmacological properties than PROTACs, such as higher membrane permeability, improved cellular uptake, and better blood-brain barrier penetration.
Molecular Glues in Clinical Trials
Molecular Glues Targeting IKZF1/3
- CC-92480 (Mezigdomide): Developed by BMS/Celgene, Mezigdomide is a novel cereblon E3 ligase modulator for the treatment of relapsed and refractory multiple myeloma (RRMM). It demonstrates stronger antiproliferative and tumoricidal activity in vitro against multiple myeloma cell lines resistant to lenalidomide and pomalidomide, along with potent immunostimulatory effects. It is currently in Phase II clinical trials (NCT05372354).
- CC-220 (Iberdomide): Also developed by BMS/Celgene, Iberdomide shows higher affinity for cereblon in time-resolved fluorescence energy transfer binding assays and greater potency in degrading IKZF1 and IKZF3 in chemiluminescent substrate degradation assays, compared to lenalidomide and pomalidomide. It was granted orphan drug designation by the FDA in December 2018 for the treatment of multiple myeloma. It is in Phase II clinical trials for RRMM, non-Hodgkin lymphoma, and systemic lupus erythematosus (NCT02773030).
- CFT7455: Developed by C4 Therapeutics, CFT7455 features a unique tricyclic imide structure that enables degradation of IKZF1 and IKZF3 via cereblon E3 ligase. It demonstrated favorable pharmacokinetic properties and oral bioavailability in preclinical studies. Currently in Phase I/II clinical trials for multiple myeloma and non-Hodgkin lymphoma (NCT04756726).
- ICP-490: Developed by InnoCare, this molecule is undergoing Phase II clinical trials for the treatment of relapsed and refractory multiple myeloma (NCT05719701).
Molecular Glues Targeting GSPT1
- CC-90009: Developed by Celgene, this was the first cereblon-based molecular glue to enter clinical development. It selectively targets GSPT1 for proteasomal degradation and is currently in Phase II clinical trials for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) (NCT04336982, NCT02848001).
- MRT-2359: Developed by Monte Rosa Therapeutics, MRT-2359 is in Phase I/II clinical trials for small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), and diffuse large B-cell lymphoma (DLBCL) (NCT05546268).
- BTX-1188: An oral molecular glue that degrades both GSPT1 and IKZF1/3. It is currently in Phase I clinical trials for hematologic and solid tumors.
Molecular Glues Targeting RBM39
- E7820: Developed by Eisai, E7820 was initially pursued as an angiogenesis inhibitor but later exhibited anti-tumor properties in mouse models. It is a novel aryl sulfonamide molecular glue degrader that recruits DCAF15 to mediate degradation of the RNA-binding protein RBM39. It is in Phase II clinical trials for relapsed or refractory AML, MDS, and chronic myelomonocytic leukemia (NCT05024994).
Molecular Glues Targeting IKZF2
- NVP-DKY709: Developed by Novartis, this selective IKZF2 transcription factor degrader recruits IKZF2 to cereblon to modulate the function of regulatory T cells (Tregs) and effector T cells (Teffs), thereby enhancing immune responses and delaying tumor growth. It is currently in Phase I clinical trials as an immunomodulatory agent for cancer immunotherapy (NCT03891953).
Others
- DEG6498: Developed by China-based Degron Therapeutics, this molecular glue targets human antigen R (HuR) by inducing its interaction with cereblon E3 ubiquitin ligase, promoting HuR degradation. It has received FDA approval to enter early-stage clinical trials, which will assess its safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity in patients with various solid tumors.
- IK-595: A MEK/RAF-targeting molecular glue, supported by the NCI, currently under clinical investigation for its potential efficacy in cancer therapy.
Applications of Molecular Glues
- Cancer: Molecular glues such as thalidomide and its derivatives, lenalidomide and pomalidomide, have played a critical role in treating multiple myeloma by inducing the degradation of specific proteins in tumor cells, thereby inhibiting their growth and proliferation. In addition, molecular glues are showing increasing promise in the treatment of solid tumors, with ongoing research targeting proteins such as GSPT1, RBM3, and PRMT5.
- Autoimmune Diseases and Inflammation: Some molecular glues can regulate immune cell function and signaling pathways. By inducing the degradation of specific transcription factors or inhibiting key protein interactions in inflammatory signaling pathways, they can help alleviate inflammatory responses and symptoms of autoimmune diseases.
- Other Diseases: Molecular glues also hold promise in the treatment of diabetes, cardiovascular diseases, and ophthalmic conditions. For example, certain molecular glues can regulate interactions between metabolism-related proteins, influencing glucose and lipid metabolism, thus offering new strategies for managing diabetes and cardiovascular disorders.
