Frontrunners in Molecular Glues

Belgium-based Orionis Biosciences is a clinical-stage life science company developing conditionally acting medicines for cancer and other diseases. Its pipeline includes molecular glue drug modalities and targeted cytokine immunotherapies. Its proprietary allosteric molecular glues, Allo-Glues, are monovalent molecules that can target protein degradation (TPD) modulation, by inhibiting or promoting intracellular signals. Orionis’ agnostic Allo-Glues can be used to target proteins in hard-to-treat diseases, such as oncology and organ transplant rejection (1).

Technology

Molecular glues were first discovered in plants such as Arabidopsis thalian where they were found to stick proteins together (1). In 1971, researchers at Sandoz observed that Sandimmune could induce neo-protein-protein associations and impact protein degradation, and in 1983 Astellas (formerly Fujisawa) identified tacrolimus (FK506). Both agents have since been approved for use in patients to prevent organ transplant rejection (2).

Today, the most widely used molecular glues are monovalent small molecules (<500 Da) that bind to the surface of an E3 ligase receptor or DCAF15 to modulate protein degradation via the proteasome (3). However, biopharma companies have been actively screening for agents that can TPD and several classes have emerged including natural glues (e.g., FKBp12 F36V, FKBP12 PK1012, Rapamycin, Synstab A, Taxol), synthetic bifunctional glues (e.g., DDB1 Cereblon CK1a, Lenalidomide, Indisulam, Thalidomide), as well as novel proteolysis-targeting chimera (PROTAC) glues (e.g., ARV-110) and tacrolimus analogues (e.g., CEP250 FKBP12 and WD8002) (3,4).

Approved molecular glues

Several molecular glues—Sandimmune, Tacrolimus, Sirolimus, Thalidomide, lenalidomide, Taxotere—have already demonstrated good immunosuppressive efficacy and tolerability in solid tumours and as gene therapies for acute leukaemia (3,5).

Orionis has several Allo-Glue programmes that focus on cancer and immunology targets, and and initiated a Phase I trial in November 2023 with its lead candidate, ORB‑011, a cis-targeted interferon for the treatment of patients with advanced solid tumours (6).

Pharma activity

Big Pharma, including Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Merck & Co, and Novartis, have molecular glue programmes in development and forged collaborations with leaders in this field (Table I). For example, Orionis Biosciences has forged partnerships with Novartis and Genentech (7,8), and Austrian-based Proxygen has initiated collaborations with Merck & Co./MSD and Boehringer Ingelheim in multiple targets (9,10). In the United States, Nurix Therapeutics has teamed up with Seagen to combine TPD and antibody-drug conjugation (ADC) in cancer therapeutics (11).

Competitor companies

Competition is intensifying, and several Chinese and US biopharma companies are also working in this field and have products in preclinical and early clinical development. These include:

• China-based Degron Therapeutics has raised US$34.5 million (€31.5 million) in venture capital and has more than 20 projects of unique molecular glue degraders (MGDs) targeting IKZF1 and IKZF3 using its proprietary GlueXplorer platform. The company expects to file an investigational new drug (IND) in 2024 for its lead programme.
• US-based C4 Therapeutics (a spin-out from the Dana-Farber Cancer Institute) has developed its proprietary TORPEDO platform and developed MonoDAC and BiDAC degraders. Its lead candidate CFT7455 is currently in a Phase I/II clinical trial for the treatment of multiple myeloma and non-Hodgkin’s lymphomas. In 2021, CFT7455 received an orphan drug designation from the US Food and Drug Administration (FDA) for multiple myeloma (13).
• US-based Nurix Therapeutics is developing a Bruton Tyrosine Kinase (BTK) degrader, NX-5948 and NX-2129 in haematological cancer. Nurix has built DELigase, an integrated discovery platform to identify and advance novel drug candidates that can modulate proteins within the cell.
• US-based Seed Therapeutics plans to file an IND in the US in 2024 for RBM30 in oncology and has several other agents in preclinical development that target neurodegeneration, immunology, and antivirals and has established an R&D collaboration with Eli Lily (14).
• US-based BioTheryx in May 2023 presented new data on bifunctional degraders of CDK4/6 and SOS1 degraders. BTX-9341 for HER.
• US-based Magnet Biomedicine is applying its proprietary TrueGlue technology to discover new indication-agnostic treatments and has attracted US$50 million (€46 million) Series A funding to move its pipeline forward.
• US-based Monte Rosa Therapeutics has developed the QuEEN (Quantitative and Engineered Elimination of Neosubstances) targeting degrons on the surface of therapeutically relevant proteins that act as ubiquitin ligase recognition signals.
• US-based Triana Biomedicines identifying novel E3 ligases. In January 2023, it was named the most promising new company in BioSpace’s NextGen 2023.

A new era for molecular glues

TPD using molecular glues has proven to be a powerful method for targeting traditionally undruggable proteins (15). Several molecular glues have received regulatory approval and many more are under clinical evaluation for a multitude of disease targets (14,16). Big Pharma have invested in this area, and biotech start-ups have attracted investor attention. Over the next few years, molecular advances in artificial intelligence and genetic tools will help drive the discovery and validation of novel bifunctional agents that could change the way pharma modulates protein interactions. Until then, pharma and private investors will have to wait patiently to see if Orionis Biosciences and its Chinese, European, and US-competitors can overcome the off-target effects of first-generation therapies and provide a more targeted approach to protein degradation and generate small-molecule proximity-inducing reagents, such as PROTACs and other unique molecular glues to treat cancers and other diseases (17,18).

References

1. Orionis Bioscience. Engaging the Powers of Nature with Precision Drug Design. Orionisbio.com, Accessed 7 Dec. 2023.
2. Schreiber, S.L. The Rise of Molecular Glues. Cell 2021; 184(1):3–9.
3. Alabi, S. Novel Mechanisms of Molecular Glue-Induced Protein Degradation Biochemistry 2021; 60(31):2371–2373.
4. Di Stasi, A.; Tey, S.-K.; Dotti, G.; et al. Inducible Apoptosis as a Safety Switch for Adoptive Cell Therapy. N. Engl. J. Med. 2011; 365:1673–1683.
5. Békés, M.; Langley, D.R.; Crews, C.M. PROTAC Targeted Protein Degraders: The Past is Prologue. Nat Rev Drug Discov. 2022; 21:181–200.
6. Orionis Bioscience. Orionis Bioscience, Announces First Patient Dosed in Phase 1 Clinical Trial of ORB-011 in Patients with Advanced Solid Tumors. News release, 15 Nov. 2023.
7. Orionis Bioscience. Genentech Sticks Molecular Glue Deal with Orionis for $47M Upfront. News release, 10 Sept. 2023.
8. Orionis Bioscience. Novartis-Partnered Orionis Secures $55M to Push Cytokine Program into the Clinic. News release, 19 Oct. 2022.
9. Proxygen. Proxygen Announces Collaboration and License Agreements with MSD. News release, 5 April 2023.
10. Proxygen. Boehringer Ingelheim Collaborates with Proxygene. News release, 7 Dec. 2020
11. Nurix Therapeutics. Nurix Announces Strategic Collaboration with Seagen Combining Industry Leading Technologies of Targeted Protein Degradation and Antibody-Drug Conjugation to Advance an Innovative New Class of Cancer Therapeutics. News release, 7 Sept 2023.
12. Sasso, J. ACS Webinar on Molecular Glues and Targeted Protein Degradation. Webinar, 12 Oct. 2022
13. C4 Therapeutics. C4 Therapeutics Announces FDA Orphan Drug Designation for CFT7455 for the Treatment of Multiple Myeloma. News release. 11 Aug. 2021.
14. Seed Therapeutics. Pipeline. SeedTherapeutics.com, Accessed 7 Dec. 2023.
15. Fan, A.T.; Boyle, B.T.; Ferguson, F.M. A New Avenue for Molecular Glues: Rapid Discovery of an NFKB1 Degrader. Cell Chem Biol. 2023;30(4):340–342.
16. Dewey, J.A.; Delalande, C.; Azizi, S.-A.; et al. Molecular Glue Discovery: Current and Future Approaches. J Med Chem. 2023;66(14):9278–9296.
17. Sternicki, L.M.; Poulsen, S.A. Native Mass Spectrometry: Insights and Opportunities for Targeted Protein Degradation. Anal Chem. 2023. doi: 10.1021/acs.analchem.3c03853.
18. Zhang, D.; Lin, P.; Lin, J. Molecular Glues Targeting GSPT1 in Cancers: A Potent Therapy Bioorg Chem. 2023;143:107000.

About the author

Cheryl Barton is director of Pharmavision, info@pharmavision.co.uk.

Article details

Pharmaceutical Technology Europe
Vol. 35, No. 9
September 2023
Pages: 18–19, 22

Citation

When referring to this article, please cite it as Barton, C. Harnessing the Power of Oncolytic Viruses. Pharmaceutical Technology Europe, 2023, 35 (9), 18–19, 22.