Advances in Engineering RAS Binders for Cancer Therapies

Ras plays a crucial role in controlling various cellular processes by switching between active (Ras-GTP) and inactive (Ras-GDP) states with the help of specific molecules. In its active form, Ras interacts with multiple effector proteins, initiating downstream events. Humans have three Ras genes, resulting in four isoforms that have distinct expression patterns and unique functions in different tissues. Posttranslational modifications target Ras to the cell membrane, where it can form dimers and interact with effectors through common domains. Ras mutations, commonly found in pancreatic, colorectal and lung cancers, lock Ras in an active state, promoting continuous cell division and proliferation. Ras signaling disruption occurs through reduced catalytic activity, altered effector binding and decreased affinity for other regulatory proteins. Although Ras has been considered difficult to target, recent advancements have identified potential binding pockets that can be addressed by small molecules, peptidomimetics and proteins. Inhibitors designed to covalently bind to the Ras G12C mutant have shown promise, leading to FDA-approved drugs for specific lung cancers. Additionally, protein-based inhibitors that target Ras and its interactions with effectors, regulatory proteins and guanine nucleotide exchange factors offer alternative strategies for therapeutic intervention. These developments have challenged the notion that Ras is “undruggable” and highlight the potential for effective treatments against various cancer types. On July 1, 2023, researchers Atilio Tomazini and Julia M. Shifman from The Hebrew University of Jerusalem published a new review paper in Oncotarget, entitled, “Targeting Ras with protein engineering.” The authors provide an overview of the challenges associated with targeting Ras proteins with small molecules and discuss how protein engineering has emerged as a promising method to overcome these challenges. “While the development of small-molecule Ras inhibitors has been reviewed elsewhere [40], we focus our review on protein-based Ras inhibitors, describing the methods for their engineering, various scaffolds used for inhibitor design, and prospects for delivery of the designed Ras inhibitors into the cellular cytoplasm, where Ras is located.” Full blog - https://www.oncotarget.org/2023/07/14/targeting-ras-in-cancer-therapies-advances-in-protein-engineering/ Paper DOI - https://doi.org/10.18632/oncotarget.28469 Correspondence to - Julia M. Shifman - jshifman@mail.huji.ac.il Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28469 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - Ras oncogene, anti-Ras therapeutics, Ras targeting, protein engineering, protein design About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957