Since the 2014 discoveries that thalidomide-like compounds “glue” together the cereblon (CRBN) unit of the ubiquitin E3 ligase complex and certain immune cell transcription factors, molecular glue degraders have been caught up in the targeted protein degradation zeitgeist that catapulted PROTACs, their bulkier bivalent counterparts, to the forefront of drug hunters’ attention. Interest in molecular glue degraders continues to explode, with startups raising billions to fund glue degrader R&D and dozens of clinical trials involving glue degraders underway.
These monomeric small molecules are attractive not only for their ability to induce protein-protein interactions and catalytically destroy their molecular targets, but also for their more favorable physicochemical properties and associated developability compared to PROTACS thanks to glues’ comparatively small size. The imide class of molecular glue degraders, which includes pomalidomide, have been highly successful oral drugs for myeloma for years. Recent breakthroughs in understanding of the chemistry and biology of these molecules have created numerous opportunities for drugging previously underexplored targets.
Recently, scientists from CAS published a treasure trove of data, webinar, and downloadable report on the current state of molecular glue and targeted protein degradation research that shows not only how molecular glue degrader research has intensified over the last five years, but also what opportunities could drive the field’s future. Using key insights supplied from CAS, we assembled this minireview to help you quickly survey the landscape of molecule glue degraders. We’ll cover:
- The structures and indications of approved molecular glue degraders
- The structures and indications of degraders that are in clinical and pre-clinical research
- Exciting opportunities to expand the impact of this therapeutic modality
Current Molecular Glue Degraders: Approved and In the Clinic
To date, the only FDA-approved molecular glue degraders are thalidomide and its analogs, lenalidomide (Revlimid) and pomalidomide (Pomalyst). All three of these immunomodulatory imide drugs (IMiDs) are used in the treatment of multiple myeloma (among other conditions) and all recruit the CRBN domain of the E3 ubiquitin ligase complex to degrade the transcription factors IKZF1/3, among other targets. Celgene invested heavily in molecular glue degrader research prior to its 2019 acquisition by BMS, allowing BMS to become one of the dominant players in glue degrader development (Figure 1). Many of the disclosed molecular glue degraders in the clinical pipeline are built from the same core structure as the thalidomide analogs, recruit CRBN for target degradation, and are being explored to treat various cancers.
Molecular Highlights from Eight Promising Molecular Glue Degraders
We’ve taken a closer look at a collection of molecular glue degraders with disclosed structures highlighted in the CAS Insights article and 2022 Biochemistry article. The eight structures we selected are representative of the current state of this field and are all either currently undergoing clinical evaluation or are still in preclinical research.
You can download our poster summary of our highlighted molecular glue degraders below:
CC-90009 (BMS/Celgene, Ph. II, Targets GSPT1)
- CC-90009 is a CRBN-based molecular glue. It is a clinical candidate in Ph. II for AML (NCT04336982) and MDS (NCT02848001) and spares the primary targets of prior imide drugs (IKZF1/3), selectively degrading GSPT1 instead. CC-90009 is the first clinical candidate to specifically target GSPT1 for degradation.
- CC-90009 is also the first rationally designed molecular glue degrader to reach the clinic. Thalidomide, for example, was serendipitously discovered to be molecular glue degraders only after receiving FDA approval.
- The starting point for CC-90009 was identified through a phenotypic screen against a panel of AML cell lines using BMS’s CRBN modulator library.
CFT7455 (C4 Therapeutics, Ph. I/II, Targets IKZF1/3)
- CFT7455’s tricyclic imide core was revealed at the 2022 AACR meeting. After identifying an initial lead from their molecular glue degrader library, C4 Therapeutics arrived at CFT7455’s unique core by modeling candidate interactions with CRBN against existing crystal structures.
- Like thalidomide and its derivatives, CFT7455 recruits CRBN for IKZF1/3 degradation, but it is significantly more potent, demonstrating picomolar IC50 and DC50 values. CFT7455 is currently being investigated for the treatment of multiple myeloma and non-Hodgkin’s lymphoma (NCT04756726).
DKY709 (Novartis, Ph. I/Ib, Targets IKZF2)
- Unlike the IKZF1/3-targeting imide drugs discussed above, Novartis’s DKY709 selectively targets IKZF2. Interestingly, the developing team found that though pomalidomide promotes complex formation between CRBN and IKZF2, no degradation is induced, potentially due to a blocking histidine residue on IKZF2. Subsequent SAR optimization led to DKY709.
- Like CFT7455 and E7820, DKY709 is being delivered as an oral tablet in the clinic. It’s being investigated for the treatment of various solid tumors (NCT03891953).
- A partnership sealed in 2021 between Novartis and targeted protein degradation startup Dunad Therapeutics further signals Novartis’s ongoing interest in the molecular glue degrader space.
E7820 (Eisai, Inc., Ph. II, Targets RBM39)
- Eisai Therapeutics’ E7820 is one of several aryl sulfonamide molecular glue degraders in the clinic that recruit DCAF15 for the targeted degradation of RNA binding protein RBM39.
- E7820 was first developed by Eisai researchers as an angiogenesis inhibitor, but a subsequent 2004 study identified its anti-cancer properties in mice. A structurally related aryl sulfonamide, indisulam, has been studied in the clinic for treatment of patients with solid tumors. More recent studies have confirmed indisulam and E7820’s molecular glue degrader activity.
- The Ph. II study (NCT05024994) is examining E7820 for treatment of patients with relapsed or refractory AML, MDS, or CMML.
(R)-CR8 (Broad Institute/Friedrich Miescher Institute, Preclinical, Targets Cyclin K)
- Molecular glue degraders in the preclinical stage demonstrate more structural diversity than the imide and aryl sulfonamide bivalent degrader platforms that have made it to the clinic. (R)-CR8, with its adenine core, is one such example. Previously known to be a CDK inhibitor, (R)-CR8 was discovered to be a molecular glue degrader of cyclin K in 2020.
- A crystal structure of the molecular glue complex shows that (R)-CR8 acts by binding to the active site of a CDK (which binds to cyclin K) and recruits DDB1 through the molecule’s solvent-exposed pyridyl arm (PDB: 6TD3).
- (R)-CR8 was identified by mining databases for correlations between the cytotoxicity of over 4,000 small molecules and E3 ligase expression levels across cancer cell lines.
TMX-4116 (Dana Farber Cancer Institute/Stanford, Preclinical, Targets CK1α)
- TMX-4116 was developed from FPFT-2216, a structurally related molecular glue degrader that lacks TMX-4116’s cyclic amide moiety. While FPFT-2216 is able to recruit CRBN for the degradation of PDE6D, IKZF1/3, and CK1α, TMX-4116 selectively degrades CK1α.
- SJ7095, a molecular glue degrader of IKZF1/3 and CK1α was disclosed by St. Jude Research at the fall 2022 ACS meeting.
NRX-252114 (Nurix Therapeutics, Preclinical, Targets Mutant β-Catenin)
- Unlike the other molecular glue degraders covered in this review, NRX-252114 is the only one that targets a mutant protein. NRX-252114 was developed to recruit β-TrCP for the degradation of an oncogenic transcription factor, mutant β-Catenin.
- Nurix Therapeutics has several compounds for small molecule targeted protein degradation in its clinical pipeline, but structures have not yet been disclosed. They have two degraders, NX-2127 and NX-5948, that recruit CRBN for targeted degradation of BTK. Both compounds are in Ph. I clinical trials (NCT04830137 and NCT05131022) for treatment of B-cell malignancies.
BI-3802 (Boehringer Ingelheim, Preclinical, Targets BCL6)
- BI-3802 was reported in 2017 to promote degradation of BCL6, an oncogenic transcription factor in lymphomas.
- A subsequent investigation revealed a unique molecular glue degrader mechanism of action for BI-3802 involving degradation by E3 ligase SIAH1. It was found that BI-3802 induces BCL6 to polymerize and form sinusoidal protein filaments. Polymerized BCL6 shows greater affinity for SIAH1 than the BCL6 in the absence of BI-3802, which accounts for BI-3802’s degrader activity.
Further Opportunities to Target New E3 Ligases
The novel molecules shown above are exciting proofs-of-concept, but the molecular glue degrader field is still young relative to targeted protein degradation overall. There are over 600 reported E3 ligases, but only five have been recruited by reported molecular glue degraders: CRBN, DDB1, β-TrCP, DCAF15, and SIAH1. The CAS Content Collection contains hundreds of documents featuring targeted protein degradation research related to E3 ligases that have yet to be exploited for molecular glue-based degradation (Figure 4), underscoring the vast possible opportunities for this field. Harnessing new E3’s may unlock new substrate selectivity and pharmacology beyond what is available from predominantly CRBN.
Among disclosed molecular glue degraders in the clinical pipeline, only a few key protein targets are being explored. These include IKFZ1/3 and other transcription factors, cyclin K, casein kinase 1α (CK1α), G1 to S Phase Transition Protein 1 (GSPT1), RNA Binding Motif Protein 39 (RBM39), β-Catenin, and BCL6 Protein. However, the molecular glue degrader strategy is ideal for targeting otherwise difficult-to-drug proteins, including intrinsically disordered proteins that may have been historically overlooked by drug hunters.
As noted above, all of the approved molecular glue degraders and many of those in the clinical pipeline incorporate the IMiD core (examples highlighted in purple, Figure 2). Just as target and recruiter spaces are ripe for discovery, there is likely substantial chemical space to explore with molecular glues. However, the discovery and design of molecular glues poses significant challenges and robust structure-guided design, understanding of protein-protein interfaces, and general discovery principles will likely be critical.
Finally, cancers are by far the most actively studied indication for all classes of molecular glues, but as recent advances in the PROTAC clinical pipeline demonstrate, there are opportunities elsewhere. For example, PROTAC-focused startup Kymera recently released promising phase 1 clinical results for its IRAK4 degrader program in the treatment of immunological indications.
Molecular Glue Degrader and Related Companies to Watch
There are several other pre-clinical and clinical molecular glue degrader programs with undisclosed leads and targets. Some programs you should keep an eye on in 2023 include:
Monte Rosa Therapeutics’s molecular glue degrader MRT-2359 entered a Ph. I/II clinical study in fall 2022 (NCT05546268). Like BMS’s CC-90009, MRT-2359 recruits CRBN for degradation of translation termination factor GSPT1. It will be interesting to see how results from these trials compare. Monte Rosa has several other targets for molecule glue degraders that are in the discovery phase, including a program targeting NEK7 for inflammatory diseases and VAV1 for autoimmune diseases.
Startup Plexium is focused on developing monovalent and molecular glue degraders. While details are light on their current pipeline, they are developing a glue degrader candidate for IKZF2. More intriguing is their partnership with AbbVie, which was announced in April of this year, to develop targeted protein degradation therapeutics for neurological conditions.
Ambagon Therapeutics is a new startup focused on using molecular glues to drug intrinsically disordered proteins. By focusing on 14-3-3 proteins which naturally interact with phosphorylated sequences in disordered regions of partner proteins, the company plans to use molecular glues to further stabilize these interactions and promote downstream events, including degradation. While no degrader programs are explicitly in their current pipeline, given the serendipitous discovery of substrate degradation in many molecular glue research programs, the 14-3-3 platform is worth paying attention to.
At the start of 2022, Ranok Therapeutics was cleared for a Ph. I/II study of its small molecule BRD4 degrader RNK05047, which is the first BRD4 degrader to enter clinical testing. A trial initiated in August for treatment of patients with solid tumors or diffuse large B-cell lymphoma (NCT05487170). (12/27/22 NOTE: While the molecule does not have a disclosed structure and is a heterobifunctional molecule, the use of the HSP90 chaperone to drive degradation is interesting as a potential opportunity for new glue discovery. Thanks to Kanak Raina for pointing this out).
Conclusions
The robust clinical pipeline of up-and-coming molecular glue degraders and the ongoing interest in targeted protein degradation as a key therapeutic modality signals an exciting future for drug hunters. Out-of-the-box thinking about new targets and engaging with other E3 ligases, as well as innovations in screening, modeling, and monovalent drug design should keep the industry busy for years to come.
We hope you found this minireview useful. We found the recently launched CAS Insights resource hub to be a goldmine of interesting data, and this landscape overview was greatly simplified by the insights gleaned by CAS’s scientists. You can see all of the open access articles, webinars, and publications on a wide range of topics relevant to your drug discovery team here:
Additional Resources
- ACS webinar on molecular glues and targeted protein degradation
- How Molecular Glues Are Connecting Targeted Protein Degradation to the Clinic (2022 Biochemistry article)
- CAS Insights Resource Hub
- CAS Insights article: Molecular glues and induced proximity: solving the undruggable
- CAS Insights article: Are intrinsically disordered proteins the key to treating COVID-19?
- CAS Insights report: Targeted Protein Degradation and Induced Proximity: Molecular Glues Landscape in Drug Discovery
About CAS
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