Molecular glues are monovalent small molecules (<500 Da) that mainly induce or stabilize protein–protein interaction (PPI) between an E3 ligase and a target protein to form a ternary complex, leading to protein ubiquitination and subsequent proteasomal degradation.

Molecular glues are distinctly different from PROTACs. PROTACs are bifunctional molecules consisting of two ligands connected via a linker that can twist and turn and allow the two proteins to form contacts, while molecular glues can 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 the affinity of these two proteins for each other.

Compared to PROTAC, molecular glues are highly attractive in terms of druggability, with relatively smaller size and molecular weight, higher membrane permeability, better pharmacokinetic properties, and better exploitability, making them an extremely promising strategy for drug development.

Figure 1. Schematic presentation of (A) a molecular glue or (B) a PROTAC. Source: reference [1]

FDA Approved Molecular Glues

To date, the only FDA-approved molecular glues are thalidomide (Thalomid) and its analogs, lenalidomide (Revlimid) and pomalidomide (Pomalyst).

Figure 2. Approved molecular glues by FDA

Thalidomide (Thalomid): Thalidomide was approved for test marketing in Germany as early as 1956 and was successively approved for marketing in 51 countries. In 1962, thalidomide was mandatorily withdrawn from the market due to cases of fetal teratogenicity. Ongoing studies found other pharmacological effects of thalidomide, with significant efficacy in patients with erythema nodosum leprosum and multiple myeloma (MM), thus in 1998 and 2006, thalidomide was again approved and recommended by the FDA for the treatment of these diseases. Thalidomide now has multiple clinical indications and sales in the U.S. exceed $200 million annually.

Lenalidomide (Revlimid): As a derivative of thalidomide, lenalidomide has better efficacy, lower teratogenic risk and toxicity, and was approved by the US FDA and European Medicines Agency (EMA) in December 2005 for clinical use in MM and myelodysplastic syndromes (MDS).

Pomalidomide (Pomalyst): Pomalidomide, a derivative of lenalidomide, is a third-generation immunomodulator for the treatment of MM, first approved by the FDA in February 2013 and approved by the EMA in August of the same year. Compared with lenalidomide, pomalidomide has a lower therapeutic dose and lower incidence of adverse reactions, and is mainly used in MM patients who have failed lenalidomide treatment.

All three of these immunomodulatory imide drugs (IMiDs) are used to treat multiple myeloma (as well as other diseases) and all recruit the CRBN domain of the E3 ubiquitin ligase complex to degrade the transcription factors IKZF1/3 as well as other target proteins. In addition, analogs of thalidomide are also common E3 ubiquitin ligase ligands for many PROTAC molecules, such as (R)-thalidomide, which is the ubiquitin ligase ligand for ARV-471 in Phase III clinical trials.

Molecular Glues In Clinical Trials

In addition to the three approved molecular glues, more than 20 molecular glues are currently in clinical trials. BMS is undoubtedly a leader in this field, who acquired the molecular glue pipelines of Celgene in 2019, including lenalidomide (already on the market), CC-92480 (Mezigdomide), CC-99282, CC-220, etc. 

Figure 3. Molecular glues in clinical trials, source: references [2]

Mezigdomide (CC-92480) (BMS/Celgene, Ph. II, Targets GSPT1)

CC-92480 (Mezigdomide) is an Ikaros/Aiolos (IKZF1/3) degrader being developed for the treatment of relapsed refractory multiple myeloma (RRMM).CC-92480 is a novel cereblon E3 ligase modulator (CELMoD) agent designed to rapidly and maximally degrade Ikaros and Aiolos. In vitro, it has enhanced anti-proliferative and tumoricidal activity in MM cell lines, including cells resistant to lenalidomide (LEN) and pomalidomide (POM), and has potent immunostimulatory activity. A phase 1, multicenter, dose-escalation study evaluated the maximum tolerated dose (MTD) of CC-92480 + dexamethasone in heavily pretreated RRMM patients, followed by a phase 2 dose, safety, tolerability and pharmacokinetic trial after determining the optimal dose. The results showed an objective response rate (ORR) of 48% at the therapeutic dose.

Figure 4. Structure of Mezigdomide

Iberdomide (CC-220 ) BMS/Celgene, Ph. II, Targets IKZF1/3)

CC-220 (Iberdomide) was synthesized as part of BMS/Celgene's 4′-arylmethoxy isoindoline–glutarimide library. Studies show CC-220 binds to CRBN with a higher affinity than lenalidomide and pomalidomide in time-resolved fluorescence energy transfer cereblon binding assays and degrades IKZF1 and IKZF3 with greater potency in cell-based chemiluminesence substrate degradation assays.
In December 2018, Iberdomide was granted orphan drug designation by the FDA for the treatment of multiple myeloma. It is currently in development for the indications of relapsed/refractory multiple myeloma, non-Hodgkin's lymphoma, and systemic lupus erythematosus.

Figure 5. Structure of Iberdomide, source: reference [4]

CC-90009 (BMS/Celgene, Ph. II, Targets GSPT1)

CC-90009, developed by Celgene, is a CRBN-based molecular glue and the first cereblon E3 ligase modulating drug to enter clinical development that specifically targets GSPT1 (G1 to S phase transition 1) for proteasomal degradation. It is currently in Phase II clinical trials for AML ( NCT04336982 ) and MDS ( NCT02848001 ).

Figure 6. Structure of  CC-90009, source: reference [3]

E7820 (Eisai, Inc., Ph. II, Targets RBM39)

E7820, developed by Eisai, was originally developed as an angiogenesis inhibitor but subsequently demonstrated antitumor properties in mouse assays. Unlike the imide structure of lenalidomide, E7820 is a novel aryl sulfonamide molecular gel degrader that degrades the RNA binding protein RBM39 by recruiting DCAF15. It is currently in a phase II study ( NCT05024994 ) for relapsed or refractory AML, MDS or CMML.

Figure 7. Structure of E7820, source: reference [3]

CFT7455 (C4 Therapeutics, Ph. I/II, Targets IKZF1/3)

CFT7455, which was optimized by C4 Therapeutics from their library of molecular glue degraders, contains a unique tricyclic imide structure. CFT7455 degrades IKZF1 and IKZF3 that binds to CRBN E3 ligase, and exhibits favorable physiochemical properties, pharmacokinetic parameters, and good oral bioavailability in preclinical studies. It is currently in Phase I/II clinical trials for the treatment of multiple myeloma and non-Hodgkin's lymphoma ( NCT04756726 ).

Figure 8. Structure of CFT7455, source: reference [3]

NVP-DKY709 (Novartis, Ph. I/Ib, Targets IKZF2)

NVP-DKY709, a selective molecular glue degrader of the IKZF2 transcription factor that was identified on the basis of recruitment of IKZF2 to CRBN. NVP-DKY709 can modulate regulatory T cells (Tregs) and effector T (Teff) cells functions in vitro, and enhanced immune response and delayed tumor growth in vivo. It is currently being investigated in a phase 1 clinical trial (NCT03891953) as an immune-enhancing agent for cancer immunotherapy.

Figure 9. Structure of NVP-DKY709, source: reference [3]

Molecular Glues In Preclinical Development

In addition to BMS, Novartis, and C4 Therapeutics, with molecular glues in clinical investigation, companies developing preclinical molecular glues are going forward to optimize their own molecular glues in order to push them into the clinic. These include (R)-CR8 from Broad Institute/Friedrich Miescher Institute, TMX-4116 from Dana Farber Cancer Institute/Stanford, and NRX-252114 from Nurix Therapeutics, etc.

Figure 10. Molecular glues in preclinical, source: references [2]

Conclusion

While many exciting new molecular glues have been described above, the field of molecular glue degraders is still young relative to targeted protein degradation. Over 600 E3 ligases have been reported, but only five have been used for molecular glue-mediated degradation, namely CRBN, DDB1, β-TrCP, DCAF15, and SIAH1. The E3 ligase library still holds great potential to be exploited, and identification of new E3 ligase ligands could help expand the target proteins we can degrade.

In addition, the chemical space of molecular glue compounds deserves more exploration, and most of the molecular glue reported so far still has high similarity to thalidomide and its derivatives, which of course is a real challenge for drug development researchers. There is a need to deepen the insight and understanding of the protein-protein interaction interface, and to make more rational structure-oriented molecular glue designs based on this, in order to truly bring molecular glue to clinical applications and help to treat more diseases.

References:
[1] Molecular Glues: The Adhesive Connecting Targeted Protein Degradation to the Clinic, Janet M. Sasso, Rumiana Tenchov, DaSheng Wang, Linda S. Johnson, Xinmei Wang, and Qiongqiong Angela Zhou, Biochemistry 2023 62 (3), 601-623, DOI: 10.1021/acs.biochem.2c00245
[2] ACS webinar on molecular glues and targeted protein degradation
[3] https://drughunter.com/the-molecular-glue-degrader-landscape-in-2022/ 
[4] https://cen.acs.org/pharmaceuticals/drug-discovery/Molecular-glues-startups-search-beyond-PROTACS/100/i29 

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