The National Cancer Institute (NCI), under the Cancer Treatment Research Federal Grant Program (CFDA 93.395), awarded a $269,280 Project Grant (R21CA296712) to Cold Spring Harbor Laboratory (CSHL) to develop a novel targeted approach for treating K-RAS(G12C) mutation-driven cancers. The key objectives of this 2-year research project are:
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Determine the binding location and selectivity of jerantinine alkaloid compounds for covalently labeling the K-RAS(G12C) oncogenic target using mass spectrometry techniques.
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Investigate if jerantinine alkaloid-mediated covalent modification of K-RAS(G12C) leads to its degradation, and evaluate the synergistic effects of targeted protein degradation combined with the release of cytotoxic natural products.
The overarching goal is to demonstrate the selective group transfer of E3 ligase recruiting fragments to K-RAS(G12C) and the synergistic therapeutic impact of this targeted degradation coupled with the release of multi-targeting polypharmaceuticals. This research aims to address the limitations of current K-RAS(G12C) inhibitor therapies and provide a potential new approach for treating certain lung and colorectal cancers.
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