The Protein Puzzle: How can we address the challenge of undruggable proteins?

Analysis

Cancer that does not respond well to treatment is a heart-wrenching reality for thousands of people. It might be something you have personally faced or seen a loved one grapple with.

This reality is driven by so-called ‘undruggable proteins’, which have been a persistent challenge in drug development for decades. Proteins are the parts of cancer cells usually targeted by medicines, but the structure of certain ‘undruggable’ proteins have made them especially resistant to treatment.

Think of an undruggable protein as a complex lock. Historically, scientists have been unable to find the right ‘key’ to ‘unlock’ the protein, and this has meant that certain cancers remain stubbornly unresponsive despite a seemingly ever-expanding array of treatment options. Scientists have pursued various strategies to solve undruggable proteins, including the use of small molecules and antibodies. While some have shown promise, progress has been slow. Only 40 of the approximately 700 cancer-causing proteins have been successfully targeted to date.[i]

But today, offering new hope, research is advancing with innovations that show significant potential.

Intervention

One such innovation is chemoproteomics. It is an innovative approach to drug discovery that uses state-of-the-art tools to explore how drugs interact with proteins, facilitating the development of more specific and safer therapeutics.[ii]

For a drug to be effective, it must integrate seamlessly into a protein's binding site, much like how a key fits into a lock. While traditional drug discovery can be like trying numerous keys on a single lock, chemoproteomics adopts a more comprehensive approach. It assesses how a potential drug interacts with all of the around 20,000 proteins coded by the human genome. Rather than zeroing in on one protein at a time, this method evaluates many in parallel. State-of-the-art tools analyse interactions between proteins and drugs and translate the data into an extensive library of high-potential drug candidates, streamlining the discovery process and possibly revealing unforeseen drug targets.[iii]

With 90% of disease-causing proteins unable to be targeted by current therapies[iv], the scope of what chemoproteomics can achieve in modern medicine is broad.[v] Its potential applications include repurposing existing treatments, identifying drug targets, improving response rates and combatting resistance.

Leading the way forward in this field is Vividion Therapeutics, a wholly owned and independently operated subsidiary of Bayer. The company has developed an approach to chemoproteomics enriching a drug pipeline for lung, head, neck, and oesophageal cancers as well as undruggable targets in immunology, offering potential for expansion into other therapy areas.

In the words of Dr. Aleksandra Rizo, CEO of Vividion: “In oncology, we've known of many cancer-driving proteins for decades, but with the limitations of the traditional discovery approaches, we’ve been unable to drug them. Now, with our chemoproteomics platform, we have a better opportunity than ever to overcome the limitations that have held treatments back for so long, and we hope to offer a whole new range of therapeutic options for patients in the future.”

Our Prognosis

The prognosis for chemoproteomics appears to be particularly promising, as the approach has the potential to transform how we address cancer and other diseases previously untreatable with conventional methods.

Already, chemoproteomics has paved the way by screening for hundreds of novel targets. The scalability of this technology has the potential to exponentially expand the druggable space in a way that could accelerate the development of life-changing medicines for patients and their families. For individuals who have been trapped in the painful grip of untreatable cancer, these innovations could represent a step away from that heart-wrenching reality, offering hope for a better, healthier tomorrow.

References

[i] Tweardy DJ. DRUGGING "UNDRUGGABLE" DISEASE-CAUSING PROTEINS: FOCUS ON SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT) 3. Trans Am Clin Climatol Assoc. 2022;132:61-76. PMID: 36196170; PMCID: PMC9480546.

[ii] Bayer Pharmaceuticals. Keys to the Undruggable Space – Chemoproteomics. Bayer Global website. 2023. Available at: https://www.bayer.com/en/pharma/chemoproteomics-blog.

[iii] Vividion Therapeutics. Our Pipeline. Vividion website. 2023. Available at: https://vividion.com/our-pipeline/.

[iv] Oprea et al., Nature Reviews Drug Discovery, 17: 317-332, 2018.

[v] Vividion Therapeutics. Our Platform. Vividion website. 2023. Available at: https://vividion.com/our-platform/.