New synthetic monobodies target “undruggable” RAS mutations

After decades of disappointing outcomes in attempts to create drugs that can block a mutated protein associated with challenging cancers, there is now a surge in research focused on RAS proteins.

Recent breakthroughs have challenged the belief that RAS is an impossible target for drug development or that individual RAS mutations have identical effects, according to John O’Bryan, Ph.D., a researcher at MUSC Hollings Cancer Center.

Working alongside his longtime research partner Shohei Koide, Ph.D., director of Cancer Biologics at Perlmutter Cancer Center at NYU Langone, as well as other collaborators at Hollings and Perlmutter, O’Bryan has contributed to this expanding knowledge base by creating synthetic monobodies. These monobodies not only bind to KRAS(G12D), a specific RAS mutation commonly found in pancreatic, lung, and colorectal cancers, but also inhibit some of KRAS(G12D)’s activities.

Significantly, the method they used to develop these monobodies provides a blueprint for targeting other currently deemed “undruggable” mutations.

Targeting KRAS

RAS proteins serve as crucial switches in the cell, regulating signaling for various growth factor and hormone receptors.

According to O’Bryan, RAS is a vital signal relay in the cell. However, mutations cause RAS to remain constantly activated (“on”), leading to uncontrolled cell growth and eventually resulting in cancer.

O’Bryan and Koide have been collaborating on RAS research for over ten years. In their study published in the Proceedings of the National Academy of Sciences, they discuss their synthetic monobodies and reveal the structure of a hidden pocket on KRAS(G12D) that researchers are targeting as a potential entry point for cancer-fighting drugs.

O’Bryan explained that when creating a monobody, its effects are uncertain. However, it was discovered that most of the monobodies developed for RAS are inhibitory, meaning they bind to essential regions necessary for RAS function. By demonstrating their selective binding and inhibitory properties and determining their binding sites, insights into the critical functional regions of RAS can be gained.

O’Bryan noted that RAS mutations are found in approximately 20% of all human cancers and in over 90% of pancreatic ductal adenocarcinomas (PDAC), the most common type of pancreatic cancer. RAS plays a driving role in the development of PDAC, serving as one of the initiating events.

Their publication coincides with significant advancements in RAS understanding. In the past two years, the FDA approved two lung cancer drugs targeting KRAS(G12C), another frequently mutated RAS protein. This year, an early-stage clinical trial commenced for a drug targeting KRAS(G12D), made possible by the discovery of the hidden pocket by Kevan Shokat, Ph.D.

O’Bryan and Koide began their work before knowledge of the hidden pocket, conducting screenings of monobody libraries. Their monobody was found to bind around the pocket, effectively opening it up further. This suggests potential applications in drug design and development.

Their paper also outlines the structural details of the hidden pocket, which they believe will provide valuable information for the development of next-generation KRAS(G12D) inhibitors.

Furthermore, they propose that the protein engineering technologies employed in creating their monobodies could be utilized against other challenging targets, offering a more straightforward approach.

While finalizing their paper for PNAS, O’Bryan and Koide continue their individual and collaborative research on RAS.

O’Bryan received a grant from the Department of Defense to investigate the delivery of monobodies into the lungs as potential therapies. Additionally, he collaborates with Aaron Hobbs, Ph.D., a fellow researcher at Hollings who focuses on KRAS(G12R) in pancreatic cancer.

Source: Medical University of South Carolina

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