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New method could expand drug options for previously “undruggable” proteins

Diseases often arise from going haywire, yet conventional drugs have struggled to rein in these rogue elements. A promising frontier in pharmaceutical research lies with PROTACs, a novel class of drugs that show significant potential. These compounds tag proteins, earmarking them for disposal by the cell's own degradation system. Recent breakthroughs by research teams led by Herbert Waldmann at the Max Planck Institute of Molecular and Georg Winter at CeMM in Vienna unveil a fresh approach to labeling aberrant proteins for degradation using PROTACs.

This advancement opens up new avenues for expanding the rather limited array of tagging methods available, offering a broader spectrum of possibilities for precisely targeting the degradation of proteins within specific tissues.

Traditionally, many drugs have been relatively simple, small . Their mode of action often involves regulating the activity of proteins engaged in disease-related processes, a task laden with complexities. Developing these drugs requires crafting highly tailored molecules for individual proteins, akin to creating a high-security key that fits into the active center of the protein. However, this approach proves challenging for proteins only marginally involved in disease processes, leaving a substantial number of proteins deemed “undruggable.”

The game-changing aspect of PROTACs lies in their ability to guide the cell's natural disposal system to selectively eliminate problematic proteins. This innovative strategy not only widens the scope of potential targets but also introduces a more versatile tagging system. As a result, the therapeutic landscape stands to benefit from a more expansive toolkit for tackling diseases at the molecular level.

protein Ras—not undruggable after all?

Undruggable proteins, particularly in the realm of , present compelling targets for investigation. Chief among these is the diminutive Ras protein, where even a subtle alteration can irreversibly trigger uncontrolled cell growth. This oncogenic potential is underscored by Ras mutations, detected in nearly 25% of all tumors.

In a pivotal 2013 study, spearheaded by Herbert Waldmann and his team at MPI in Dortmund, a groundbreaking strategy emerged to render the once-deemed undruggable Ras, druggable. Rather than directly targeting Ras itself, the researchers devised a specialized molecule to disrupt the auxiliary protein PDEd. This manipulation influenced the transport and, consequently, the activity of Ras within the cell. Despite this innovative approach, the researchers fell short of fully halting the cancer-propagating actions of Ras.

This pioneering work not only shed light on a potential avenue for targeting Ras but also highlighted the complexity of tackling proteins previously considered impervious to therapeutic intervention. The quest to control Ras and other challenging targets in cancer research continues, propelled by evolving strategies and a deeper understanding of cellular mechanisms.

Two-armed molecule marks cancer protein for degradation

A mere two years following Waldmann's groundbreaking research, American scientists unveiled a highly promising class of drugs designed to eradicate pathological proteins, aptly named PROTACs (proteolysis-targeting chimeras). These compounds ingeniously co-opt the body's own protein disposal system. The large molecule, featuring two arms, seizes the target protein on one end and the E3 ligase of the protein waste system on the other. This dual interaction triggers the waste system to efficiently eliminate the problematic protein.

Herbert Waldmann commends this scientific feat, emphasizing its ingenuity, stating, “Instead of navigating the intricacies of inhibiting the enzymatic activity of the target protein, PROTACs simply need to bind to their target with remarkable selectivity.” He underscores the universal applicability of this principle to all proteins, a concept validated in their recent work involving the Ras transporter PDEd. This streamlined approach holds immense potential for revolutionizing by providing a versatile strategy applicable across a spectrum of proteins.

Serendipitous discovery opens up new possibilities

Drs. Waldmann and Winter, along with their research teams, have developed a novel PROTAC by integrating their PDEd inhibitor. This inhibitor, when linked to a well-explored molecule known to trigger an alternative degradation system capable of processing larger cell components, yielded intriguing results published in Nature Communications.

Contrary to expectations, the newly created PROTAC didn't activate macroautophagy, as initially hypothesized, but instead engaged the protein degradation system. Georg Winter elaborates, “What makes our PROTAC particularly noteworthy is its binding to a previously untargeted ligase, expanding the scope of the PROTAC strategy.”

Currently, only two E3 ligases are practically utilized as binding sites for PROTACs, despite the human body harboring over 600 E3 ligases. Notably, some of these ligases are confined to specific tissues. Herbert Waldmann envisions the future application of tissue-specific ligases for precisely controlling drug activity sites.

The serendipitous discovery opens avenues for further in biological and medicinal-chemical realms, specifically delving into the newfound ligases. This exploration holds the potential to diversify the arsenal of pharmaceutically viable PROTACs, ultimately paving the way for targeted protein degradation in specific tissues. In essence, this discovery marks a promising stride toward advancing in the realm of .

Source: Max Planck Society

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