PROTACs And Molecular Glues: Rethinking What Is Possible

By Steve Fawell, AstraZeneca

In drug discovery, “undruggables” are proteins or biomolecules identified as playing a role in the development or progression of diseases – such as cancer – but are challenging to target pharmacologically.¹ With the development of novel precision medicines and innovative therapeutic approaches, we are making great progress in overcoming various factors that make these targets undruggable, with new options for patients on the horizon.

Previously, I dove into the historical challenges faced by researchers trying to address undruggable targets in oncology. Here, I’ll explore the potential of novel small molecule approaches, including PROteolysis TArgeting Chimeras (PROTACs) and molecular glues, and how they work.

Despite having distinct chemistry and binding kinetics, both PROTACs and molecular glues leverage chemically-induced proximity within the cell to reprogram a target protein’s biology for therapeutic benefit.² More specifically, these modalities promote or stabilize the interaction of two cellular proteins, with one being a target protein that plays a key role in disease progression.² By doing so, they offer the opportunity to make the undruggable druggable, potentially transforming the treatment landscape for patients living with cancer, including those with aggressive or treatment-resistant tumors.³

The Rise Of PROTACS: A Versatile Game-Changer

The first of these promising small molecule approaches is PROTACs, highly specific molecules that degrade unwanted or harmful proteins in cells.⁴ These bifunctional molecules have two heads connected by a linker, with one head dedicated to binding the target protein of interest, ideally with high affinity and specificity.⁴ The other head of the molecule is reserved for an E3 ubiquitin ligase such as cereblon or von Hippel-Lindau (VHL), enzymes involved in a protein degradation pathway, which regulate the stability and function of proteins.⁴

By linking these heads together via a PROTAC molecule, we can harness the cell’s natural protein degradation machinery – the ubiquitin proteasome system.⁴ When the E3 ubiquitin ligase is brought into contact with the disease-causing target of interest it can tag the target protein with ubiquitin, which in turn marks it for degradation by the proteasome, a cellular structure described as the “cell’s trash disposal”.⁴ This highly targeted mechanism of degradation offers an advantage over traditional small molecule inhibitors.⁴

For a PROTAC molecule, the biological effect is driven by the binding to the target protein and, thereafter, the degradation event.⁵ By contrast, traditional small molecules need to both bind and have functional activity to drive the biological effect.⁵ Importantly, this intrinsic mechanistic differentiation means PROTACS have the potential to succeed in turning the undruggable to druggable.

So far, the ligases cereblon and VHL have been the most commonly used to drive the degradation, but they come with limitations such as degradation efficiency for certain target proteins.⁵ This has prompted researchers to identify additional ligases to incorporate into PROTACs and to leverage their tissue-specific expression to enable tissue-specific target protein degradation, thereby minimizing unwanted activity or toxicities.⁵

There are currently no approved PROTAC medicines, but there are several molecules in the clinic.⁵ We believe it’s only a matter of time until the first PROTAC therapy is available for treating cancer.

Molecular Glues: A Mediator In Drugging The Undruggable

The second promising modality with the potential to change what is possible with undruggables is molecular glues. These are not limited to degrading target proteins and, in contrast to PROTACs, do not have two independent binding entities.² These small molecules promote the interaction between an effector protein (such as a cellular enzyme like E3 ligase) or a chaperone (such as cyclophilin A involved in cell signaling) to form a complex with the target protein.² Depending on the effector protein, the pharmacological effect of molecular glues can be inhibition or activation or, in a manner like PROTACs, degradation.²

In the treatment of diseases like cancer, molecular glues have the potential to modify, hinder, or degrade disease-causing proteins.² The modality was first discovered during a study on mechanism of action of natural product drugs, such as the immunosuppressant cyclosporin.² For example, cyclosporin binds to the cellular chaperone protein cyclophilin A and subsequently forms a ternary complex with calcineurin, which has various important physiological roles including in T cell activation, transcription regulation, and apoptosis.⁶ The cyclosporin–cyclophilin A complex then inhibits the immune modulation function of calcineurin, an otherwise undruggable protein by traditional small molecule approaches.⁶

Another example can be seen with immunomodulatory imide drugs (IMiDs). IMiDs act as molecular glues and mediate ternary complex formation with the E3 ligase cereblon and transcription factors Ikaros and Aiolos; these are attractive targets in myeloma and other B cell malignancies yet remain undruggable by traditional approaches.⁷ In this case, the effector protein is cereblon, and the molecular glue mediated ternary complex formation leads to the degradation of Ikaros and Aiolos – making the modality a molecular glue degrader.⁷

Unlike PROTACs, approved molecular glue therapies exist, including cyclosporin, rapamycin, and IMiDs.⁸ The modality has enormous potential to tackle high-value but previously undruggable drug targets. Several biotechnology and pharmaceutical companies are currently exploring novel molecular glue drug candidates in oncology and neurology clinical trials.⁹

Benefits Over Traditional Approaches

With their differentiated pharmacological response, PROTACs and molecular glues have great potential to target the undruggable.³ Both modalities can degrade an entire disease-causing target, producing a precise, longer-lasting biological effect, and have the potential to overcome certain resistance mechanisms.³

Above all, the enhanced specificity and diverse range of these modalities create advantages.⁵ While traditional approaches typically target well-defined binding sites that are needed to exert therapeutic effect on a protein, these novel molecules have the potential to effectively target proteins with shallow binding sites – opening a door to new therapeutic targets.⁵

How PROTACS And Molecular Glues Are Starting To Transform Oncology

While PROTACs and molecular glues hold immense promise, they are still new. PROTACs only recently progressed from the lab into the clinic, where we’ll gain a deeper understanding of their potential and how to use them. The ultimate proof remains to be seen; however, recent clinical data presented by one of the PROTAC pioneers, Arvinas, confirms that these molecules can have good drug-like properties, bioavailability, pharmacokinetics, and most importantly promising signs of clinical activity.¹⁰

Given the growing successes in the field, other companies, including AstraZeneca, have increased their research and investment, focusing on a series of promising new oncology targets. To continue bringing these potentially transformative new medicines to patients, it will be critical for researchers and the industry to remain committed to the challenging research of pursuing high-value undruggable targets. Together, we have the potential to forge a new path forward in oncology drug development and deliver new solutions for those living with cancer.

This article was written and developed by AstraZeneca.

References

1. Coleman N, Rodon J. Taking aim at the undruggable. American Society of Clinical Oncology Educational Book. 2021;41: e145-e152.
2. Sasso JM, Tenchov R, Wang D, et al. Molecular glues: the adhesive connecting targeted protein degradation to the clinic. Biochemistry. 2023;62:601-623.
3. Burke MR, Smith AR, and Zheng G. Overcoming Cancer Drug Resistance Utilizing PROTAC Technology. Front Cell Dev Biol. 2022; 10.
4. Beck H, Härter M, Haß B, et al. Small molecules and their impact in drug discovery: A perspective on the occasion of the 125th anniversary of the Bayer Chemical Research Laboratory. Drug Discovery Today. 2022;27(6):1560-1574.
5. Konstantinidou M, li J, Zhang B, et al. PROTACS – a game-changing technology. Expert Opin Drug Discov. 2019;14(1):1255-1268.
6. Ke H, Mayrose D, Belshaw PJ, et al. Crystal structures of cyclophilin A complexed with cyclosporin A and N-methyl-4-[(E)-2-butenyl]-4,4-dimethylthreonine cyclosporin A. Structure. 1994; 2(1):33-44.
7. Cippitelli M, Stabile H, Kosta A, et al. Role of Aiolos and Ikaros in the Antitumor and Immunomodulatory Activity of IMiDs in Multiple Myeloma: Better to Lose Than to Find Them. Int J Mol Sci. 2021;22(3):1103.
8. Schreiber SL. The rise of molecular glues. Cell. 2021;184(1):3-9.
9. Békés M, Langley DR, Crews CM. PROTAC targeted protein degraders: the past is prologue. Nat Rev Drug Discov. 2022;21:181-200.
10. Arvinas. Potential of Arvinas’ PROTAC AR Degraders Reinforced by 11.1 months rPFS with Bavdegalutamide and Updated Positive Interim Data from Second Generation ARV-766 in mCRPC [press release]. https://ir.arvinas.com/news-releases/news-release-details/potential-arvinas-protacr-ar-degraders-reinforced-111-months . Published October 22, 2023. Accessed January 24, 2024.

About The Author:

Steve Fawell is vice president, head of oncology discovery, oncology R&D, at AstraZeneca. He applies his expertise in small molecule and biologics discovery to develop novel, innovative medicines for previously intractable and undruggable targets, with a focus on tumor drivers and resistance, DNA damage repair, and epigenetics. At AstraZeneca, he leads a department of over 400 scientists focused on target selection, drug discovery, and optimization, overseeing biology, pharmacology, DMPK, and chemistry teams. Prior to AstraZeneca, he served in leadership roles at Merck, Novartis, and Biogen and has taken more than 30 drug candidates to clinic to date. Fawell has a Ph.D. from the University of Leeds, UK, and completed postdoctoral fellowships at Rutgers Medical School New Jersey and the Imperial Cancer Research Fund (now Cancer Research UK) in London.

→Editor's Note: Check out the other two articles in this Drug Discovery Online series by Steve Fawell:

• Understanding Undruggable Targets: Challenges And Progress
• Drugging The Undruggable: Strategies And Future Directions