Mutational activation of Ras proteins and the subsequent constitutive signaling downstream drives uninhibited proliferation and promotes migration and invasion. Mutations impair intrinsic Ras activity 4, preventing GTP hydrolysis and resulting in constitutively active Ras capable of binding effector proteins including Raf 5 and PI3K 6. This is primarily due to its disordered active site and smooth surface lacking well-defined drug-binding pockets 2, 3. Given the high level of incidence across a large subset of cancer types and the well-established role of Ras in tumor initiation, development, and progression, a large effort in Ras inhibitor development has been put forth 1, 2, 3.ĭespite decades of research, however, no drugs directly targeting Ras are currently available. Known to initiate cell transformation and drive oncogenesis, mutant Ras proteins have been shown to promote tumor maintenance as well. GTPases K-Ras, H-Ras, and N-Ras comprise the most frequently mutated family of oncoproteins in human cancers, including three of the most lethal forms, cancers of the lung, colon, and pancreas. Unlike the polar interfaces found for Ras/effector interactions, the K-Ras/R11.1.6 complex reveals an extensive hydrophobic interface that can serve as a template to advance the development of high affinity, non-covalent inhibitors of K-Ras oncogenic mutants. Most importantly, this work makes an unprecedented contribution to Ras research in inhibitor development strategy by revealing details of a targetable binding surface. Our results support greater consideration of the state of switch I and provide a novel tool to study Ras biology. R11.1.6 directly blocks interaction with Raf and reduces signaling through the Raf/MEK/ERK pathway. Crystal structures of the protein R11.1.6 in complex with K-Ras WT and K-Ras G12D offer insight into the structural basis for specificity, highlighting differences in the switch I conformation as the major defining element in the higher affinity interaction. This is the first reported inhibitor to achieve nanomolar affinity while exhibiting specificity for mutant over wild type (WT) K-Ras. Here we report the engineering of a protein scaffold for preferential binding to K-Ras G12D. Its mutants, present in about 30% of human cancers, are major drivers of oncogenesis and render tumors unresponsive to standard therapies.
Ras is at the hub of signal transduction pathways controlling cell proliferation and survival.
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