Understanding Undruggable Targets: Challenges And Progress

By Steve Fawell, AstraZeneca

Undruggable — it’s a word that has haunted drug discoverers across all types of diseases for many years, especially in oncology.¹ Undruggable targets for cancer often refer to specific proteins or biomolecules that play a role in the development and progression of cancer and have evaded treatment with currently available therapies.¹ They may play a key role in directing signaling molecules involved in disease progression, be proteins with scaffolding functions, or be transcription factors.¹ They also can be part of complex multiprotein structures or have poorly defined binding sites that make it difficult to target them therapeutically.¹

Many of these targets defined as undruggable have been known as high value for decades following extraordinarily strong biological validation.¹ However, they remain untouched by conventional therapies, including small molecules.¹ Some of the most recognizable include RAS, p53, MYC, and β-catenin.² We have an intimate understanding of their roles in cancer but have only recently been able to think of tapping into their clinical utility to harness emerging treatment approaches.²

Understanding The Undruggable Problem

To understand why these targets remain undruggable, it’s important to understand how earlier generations of targeted therapies work. Conventional small molecule inhibitors typically target well-defined pockets where they bind to active sites on enzymes or cell surface receptors on cancer cells to inhibit their growth and potentially eliminate a tumor.³ While we have achieved remarkable success with these therapies, there are now many more interesting targets available to us in cancer biology.³

As we continue to discover new treatment approaches, we need to go beyond targeting proteins with accessible, well-defined pockets and find ways to selectively bind to less accessible binding sites but still with high potency.⁴ These so-called undruggable targets often have shallow cavities or poorly defined binding sites with functional relevance, making it difficult for small molecules to interact with them to exert their desired therapeutic effect.⁴ For example, many non-enzymatic proteins, including scaffolding and regulatory or structural proteins, have poorly defined binding sites with their function driven by protein-protein interactions, which typically involve larger, more diffuse contact areas.⁴ More challenging still are the class of proteins called transcription factors, which regulate gene expression and have long been considered undruggable given the lack of understanding of their structure and lack of tractable binding sites.⁵ Among the most notable transcription factors, the MYC oncogene plays a fundamental role in cell growth and is overexpressed in many human cancers, but outside of the DNA binding domain it has an intrinsically disordered protein structure which makes it difficult to target.^5,6

Today's biologics and cell therapies bind to targets that are restricted to the extracellular space, which means they can’t directly access intracellular targets.⁷ The relatively new field of T cell receptor cell therapies is showing great potential, however, through the ability to recognize intracellular targets when presented as peptides on the cell surface by Class 1 major histocompatibility complexes that have an important role in the immune response.⁷

Several other approaches to reach challenging intracellular targets, such as oligonucleotides, have struggled to succeed in oncology because of the lack of adequate tumor exposure and inefficient cell penetration and target engagement.⁸ A new wave of small molecules that directly target transcription factors, such as MYC and p53 or the RNA of an undruggable protein, show promise but are still early in development.⁹

With efforts such as the Cancer Dependency Map, which capture the genetic landscape of cancer vulnerabilities across all tumors, and the advent of CRISPR-based target validation, which allows scientists to understand the functional relationship between a gene target and a specific disease, we have identified a number of interesting new targets.¹⁰ These cover many target classes but, interestingly, many are, in fact, transcription factors.¹¹

However, current target validation approaches typically assess what happens if the gene target is deleted and, therefore, the protein involved in disease progression is lost completely.¹² Often when the target is inhibited pharmacologically, the observed effect is not the same as during validation.¹² In this scenario, a small molecule probe that is able to selectively bind and degrade the target protein would be optimal to mimic the validation approach.¹² Fortunately, the evolving field of small molecule induced targeted protein degradation has bridged this gap and we can now both validate new targets and unlock therapeutic opportunities for previously undruggable proteins.¹²

These advances in novel small molecule drug modalities have created a new path forward. We are discovering new ways of targeting oncogenes and degrading proteins, paving the way for an era of drug discovery where we can reach intracellular disease-causing targets and specifically degrade them, turning the undruggable, druggable.¹

Druggable Developments With PROTACs And Molecular Glues

Researchers have made great progress in expanding the industry’s drug discovery toolkit to develop novel precision medicines, including small molecules with unique modes of action.³

Two approaches that show incredible promise are PROteolysis TArgeting Chimeras (PROTACs) and molecular glues.³ AstraZeneca and other industry leaders have been actively involved in the research of these novel therapeutic approaches in oncology.

PROTACS are highly specific bifunctional molecules with two independent binding groups connected by a linker.³ One end of the molecule binds to a target protein of interest, and the other end binds to an E3 ligase such as Cereblon or von Hippel-Lindau, enzymes involved in a protein degradation pathway.³ Compared to traditional small molecule inhibitors that rely on deep drug-binding cavities to exert their therapeutic effect, PROTACs’ novel mode of action enables targeting relatively weaker binding sites.¹³

Molecular glues are small molecules that penetrate the cancer cell and bring together proteins that would not normally – or only weakly – interact with each other.¹⁴ This could include target proteins involved in disease progression and induce their proximity to other cellular enzymes or chaperones.¹⁴ When used to treat cancer, molecular glues have the potential to activate, inhibit, or degrade disease-causing proteins.¹⁴ It is their ability to reprogram the cellular biology of target proteins, for example, induce degradation, that is of central interest in oncology.¹⁴ Traditional drugs commonly work by inhibiting the activity of a specific protein involved in tumor growth.¹⁴ However, this inhibition may be insufficient and can, unfortunately, develop into drug resistance if the target protein undergoes mutations to resist inhibition.¹⁴ PROTACs and molecular glue degraders, on the other hand, go a step beyond and degrade these proteins via the cell’s natural protein degradation machinery, the ubiquitin-proteasome system.¹⁴ This changes the nature of the emerging resistance and opens new possibilities for how we may wish to approach it to overcome it.¹⁴

The Future Is Druggable

With PROTACs, molecular glues, and the host of new approaches being integrated into our cancer therapeutic paradigm, we’re one step closer to eliminating “undruggable” from the drug discovery lexicon. We are entering an era where our concept of what proteins can be successfully drugged has expanded significantly. The road ahead will require dedication and determination in the lab as many targets remain challenging to address, but investment in platform and molecular approaches will enable novel drug discovery that can make a difference. To continue bringing these potentially transformative new medicines to patients who need them most, it is critical we continue working together to rethink what is possible as we pursue high-value undruggable targets.

References

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9. Henley MJ, Koehler AN. Advances in targeting ‘undruggable’ transcription factors with small Molecules. Nat Rev Drug Discov. 2021;20:669-688.
10. Broad Institute. Cancer Dependency Map Consortium accelerates research into tumor vulnerabilities. https://www.broadinstitute.org/news/cancer-dependency-map-consortium-accelerates-research-tumor-vulnerabilities. Accessed December 17, 2023.
11. Tsherniak A, Vazquez F, Montgomery PG, et al. Defining a cancer dependency map. Cell. 2017;170(3):564-576..
12. Yoon H, Rutter JC, Li Y, et al. Induced protein degradation for therapeutics: past, present, and future. J Clin Invest. 2024;134(1):e175265.
13. Konstantinidou M, li J, Zhang B, et al. PROTACS – a game-changing technology. Expert Opin Drug Discov. 2019;14(1):1255-1268.
14. Sasso JM, Tenchov R, Wang D, et al. Molecular glues: the adhesive connecting targeted protein degradation to the clinic. Biochemistry. 2023;62:601-623.

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:

• PROTACs And Molecular Glues: Rethinking What Is Possible
• Drugging The Undruggable: Strategies And Future Directions