Guest Column | March 7, 2024

Drugging The Undruggable: Strategies And Future Directions

By Steve Fawell, AstraZeneca


We recently described how advances in small molecule drug discovery are allowing us to rethink and expand the list of therapeutic targets that may be druggable in oncology.1 This includes progress with platforms like PROteolysis TArgeting Chimeras (PROTACs) and molecular glues, which are opening new possibilities for targeting “undruggable” proteins that have long been known to play a role in cancer.1–5 (Check out my first two articles in this series: Understanding Undruggable Targets: Challenges And Progress and PROTACs And Molecular Glues: Rethinking What Is Possible.)

However, the progress with these new modalities hasn’t come without challenges, particularly in identifying the right chemistry starting point for drug development — a process known as hit discovery.6,7 Other hurdles also need addressing in developing high-quality drug candidates, such as understanding the underlying pharmacology and how it translates from preclinical studies to human.1 It’s fair to say, therefore, that the emerging, differentiated biology of these modalities is proving a challenge for the methods that we often use to answer key questions in drug development.

Unlocking New Targets For Emerging Modalities

The good news is that in some cases, we are also finding synergies between emerging biology and novel methodologies. One such example is CRISPR-based screening, which offers an opportunity to expand the list of undruggable targets involved in the development and progression of cancer by identifying previously untapped biology.8

The advantage of applying CRISPR during the discovery of PROTAC and molecular glue approaches is that CRISPR gene knockdown definitively confirms the functional relationship between a gene target and the disease.7 This means that genome-wide CRISPR screens, which identify novel targets based on gene knockdown, resemble the effect of degrader approaches such as PROTACs and molecular glues and help us predict how they are likely to translate into in vivo models and the clinic.1,2,8

Such target identification approaches add to the knowledge gained from platforms such as the Cancer Dependency Map, which captures the genetic landscape of cancer vulnerabilities across all tumors and increases our chances of homing in on new transformational targets.9 But while CRISPR lends itself to identifying suitable targets, we face a challenge when we try to find a way to drug the targets and establish a suitable chemical starting point for their development.8,9

Finding The Right Chemistry: Strategies For Hit Discovery

While traditional small molecule drugs typically involve a single target and a single molecule, new modalities like PROTACs and molecular glues are more complex and modular, with additional considerations needed to discover them.

To achieve this for PROTACs, researchers are leveraging existing technologies to identify binding ligands for both the target protein and, in some cases, E3 ubiquitination ligase, the part of the PROTAC driving target protein degradation.2–5,7,10 This includes traditional small molecule high-throughput screening and DNA-encoded library (DEL) screening approaches. DEL is especially suited for PROTACs, with the ability to efficiently screen billions of compounds to assess “druggability” and identify ligands that recognize binding sites on the target protein.5  

At AstraZeneca, we’ve created a “PROTAC toolbox” to accelerate the identification of PROTAC molecules.11 We are working to build a library of linker molecules and E3 ligase-recruiting motifs — both critical components of PROTACs — that can be synthetically connected to ligands that bind to disease-relevant target proteins. This plug and play process can be used to rapidly create a novel PROTAC library against a given protein target and to screen for cellular degradation. The hits that show degradation of the disease-relevant target protein are investigated further for potency, degradation efficiency, and other drug-like properties to accelerate the journey to a PROTAC-based clinical drug candidate.

How we screen to identify molecular glues is a more complex process. First, we need to decide which part of the molecular glue we are screening for. If we are screening for an effector protein, the focus is on identifying compounds that “glue” and induce a ternary complex between the effector protein and the target protein.7 This approach has so far been successful with effector proteins such as cereblon and cyclophilin A, where the chemistry for binding the proteins is well known. In contrast, if we are screening for the “interactome,” the set of molecular interactions between the effector and the target protein, we are not reliant on effector chemistry and can instead focus on identifying molecules that stabilize or catalyze a relatively weak interaction between the two so that it can be leveraged therapeutically.7

To be able to identify new molecular glues, it’s critical we develop screening assays that are sensitive enough to detect weak interactions between the effector and target protein and that also support high-throughput screening of diverse libraries of molecules.7 Screens to identify molecular glues that can stabilize a ternary complex can be explored biochemically, in cell lysates, or in the cellular context using various assay technologies.7 Importantly, the goal is to screen in a way that is biased for identifying a molecular glue for a particular target protein and thus represents a paradigm shift in thinking, moving from “is a target druggable?" to “is the target protein-effector pairing assayable?”1

The Challenge Of Developing High-Quality Drug Candidates

While it’s exciting that we are building new scientific capabilities to solve the undruggable conundrum, we must also overcome new challenges associated with novel modalities, such as PROTACs and molecular glues, in compound optimization and in drug development.

Molecules known as “leads” that show promise in screening assays in the lab typically require significant optimization with preclinical models to translate into efficacious medicines in the clinic.7 For this reason, lead optimization is an iterative process focused on parameters such as target potency, pharmacokinetic properties, and toxicology profile.3 Combining these core elements into a single molecule provides confidence that a drug candidate, when administered to patients in the clinic, will produce the intended therapeutic benefit with minimal side effects.1,3 While we have a robust understanding of how preclinical profiles of traditional small molecules predict and translate into the clinic, we have only just begun to build a similar knowledge base for these new modalities.3,12

To add to the challenge, for us to understand the potential side effects of PROTACs and molecular glues in normal tissues, we need to consider not only the target protein but also the biological activity of the E3 ligase or the effector protein.2,13 This includes carefully evaluating its protein expression ratios in disease tissue relative to normal tissues. To enable a comprehensive understanding of the pharmacology, such protein expression studies need to happen alongside drug exposure assessment when choosing a preclinical species. Beyond protein expression, we need to also consider protein homology across species to ensure on-target effects are interpretable in preclinical models, as subtle differences may have an impact on the activity of the PROTAC or molecular glue modality. In some cases, these considerations limit the choice of preclinical species, a challenge best factored in earlier in development.3

Finally, since PROTACs and molecular glues degrade proteins in the cell, it’s important to know how specific the degradation event is. Mass spectrometry-based proteomics, as a powerful method for studying the on- and off-target effects of PROTACs and molecular glues, can achieve this.2,4,7 The method is suitable for both in vitro and in vivo experiments, and it provides a comprehensive understanding of selectivity and potential toxicities.2,4,7 With the continued advances in mass spectrometry technology, which promise to expand proteome coverage and enhance assay throughput, we expect proteomics to play an even more central role in the future in profiling and prioritizing PROTACs and molecular glues for development.

Working Together To Pursue Undruggable Targets

It’s a truly exciting time for PROTACs and molecular glues, which are bringing us a step closer to eliminating “undruggable” from the drug discovery lexicon.

While more challenges lie ahead, continued investment in development and improved molecular toolkits will in time enable novel drug discovery using these advanced modalities.

Looking at what’s next, transcription factors are likely one of the biggest untapped opportunities, with many implicated as cancer targets. Pursuing them could provide significant benefits to patients where transcription-related pathways and molecules have pivotal roles in disease progression.1

As researchers, the responsibility to bring such potentially transformative new medicines to patients rests on our shoulders. I believe we can only achieve this by continuing to forge partnerships between academia and industry. It’s incredibly motivating to see some of the early strategies show results, and I am confident that with continued dedication to the pursuit of science, together we can find improved solutions for those living with cancer.

This article was written and developed by AstraZeneca.


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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.