Targeting the Undruggable: A Structure Guided Approach to Targeting KRAS

Date
2021
Authors
Touhami, Rim
Ranganathan, Srivathsan
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Cancer Early Detection Advanced Research (CEDAR), Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon KRAS gene mutations have been found in up to one-fourth of lung cancer cases, as well as colon and pancreatic cancer [1] . The KRAS gene belongs to the Ras family of oncogenes, which can be involved in transformation of normal cells into cancerous ones under certain circumstances. The KRAS gene encodes for the GTPase protein called K-Ras, whose objective is to relay outer-cell signaling to the cell’s nucleus instructing cell growth and proliferation, or differentiation [2] . Mutations have been shown to lead to uncontrollable cell growth and cancer progression [3]. Although decades of treatment research have been performed, there still remains a challenge in developing a drug directly targeting K-Ras [5]. This is due to its subtle changes in the structure of the mutated protein, as well as its intracellular location [1,5]. Sole success in targeting KRAS has been achieved through small molecules, however this method is still presented with challenges such as low binding affinity. Another promising venue to developing allele-specific inhibitors against KRAS has been found through protein scaffolds. Protein binders can be engineered to bind targets with high affinity and specificity and because of their small size, they are well suited for targeting proteins within cells [5,6]. This was illustrated by the inhibitor R11.1.6, engineered in a study by M.I.T [5] . This project focuses on the development of novel protein binders to KRAS using known 3D structure guided approach. There are hundreds of known KRAS structures with interacting partners, including GAP & GEF proteins, with KRAS in various conformational states. This information is a very good starting point for identifying peptide binders that could be evolved into high affinity reagents for targeting KRAS mutants. This research will also shed light on K-Ras interactions, while providing insight into targeted drug treatment for K-Ras.

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