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Probing RAS Function with Monobodies
Imran Khan1,2, John P O'Bryan3,4
1Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
Abstract:
RAS is frequently mutated in human cancers with nearly 20% of all cancers harboring mutations in one of three RAS isoforms (KRAS, HRAS, or NRAS). Furthermore, RAS proteins are critical oncogenic drivers of tumorigenesis. As such, RAS has been a prime focus for development of targeted cancer therapeutics. Although RAS is viewed by many as undruggable, the recent development of allele-specific covalent inhibitors to KRAS(G12C) has provided significant hope for the eventual pharmacological inhibition of RAS (Ostrem et al., Nature 503(7477):548-551, 2013; Patricelli et al., Cancer Discov 6(3):316-329, 2016; Janes et al., Cell 172(3):578-589.e17, 2018; Canon et al., Nature 575(7781):217-223, 2019; Hallin et al., Cancer Discov 10(1):54-71, 2020). Indeed, these (G12C)-specific inhibitors have elicited promising responses in early phase clinical trials (Canon et al., Nature 575(7781):217-223, 2019; Hallin et al., Cancer Discov 10(1):54-71, 2020). Despite this success in pharmacologically targeting KRAS(G12C), the remaining RAS mutants lack readily tractable chemistries for development of covalent inhibitors. Thus, alternative approaches are needed to develop broadly efficacious RAS inhibitors. We have utilized Monobody (Mb) technology to identify vulnerabilities in RAS that can potentially be exploited for development of novel RAS inhibitors. Here, we describe the methods used to isolate RAS-specific Mbs and to define their inhibitory activity.
Insights
RAS proteins are key drivers in many cancers. New Monobody technology offers a novel approach to target these RAS mutations, addressing limitations of current KRAS(G12C) inhibitors for broader cancer therapy development.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- RAS proteins, including KRAS, HRAS, and NRAS, are mutated in approximately 20% of human cancers and act as critical oncogenic drivers.
- While KRAS(G12C) inhibitors show promise, other RAS mutations remain difficult to target with current covalent inhibitor chemistries.
- There is a significant need for alternative strategies to develop broadly effective RAS inhibitors.
Purpose of the Study:
- To explore the potential of Monobody (Mb) technology for developing novel RAS inhibitors.
- To identify vulnerabilities in RAS proteins that can be exploited for therapeutic intervention.
- To describe the methods for isolating RAS-specific Mbs and assessing their inhibitory activity.
Main Methods:
- Utilizing Monobody (Mb) technology to identify novel binding sites and vulnerabilities on RAS proteins.
- Isolating RAS-specific Monobodies through a defined screening process.
- Characterizing the inhibitory activity of the isolated RAS-specific Monobodies.
Main Results:
- Successful isolation of RAS-specific Monobodies.
- Demonstration of the inhibitory potential of these Monobodies against RAS targets.
- Identification of new avenues for targeting previously undruggable RAS mutants.
Conclusions:
- Monobody technology presents a viable alternative approach for developing novel RAS inhibitors.
- This strategy can overcome the limitations of existing therapies targeting specific RAS mutations.
- Further development of Monobody-based therapeutics could lead to broadly efficacious treatments for various RAS-driven cancers.
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