Evaluating Cytotoxic Activity of KRAS-Targeted Peptoids

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2022-04-14

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The KRAS mutation is common in many types of cancer but is especially relevant to non-small cell lung cancer (NSCLC), appearing in 25% of adenocarcinomas. KRAS causes exaggerated signaling, which results in excessive cell growth and tumor formation. It is currently considered “undruggable� because the KRAS proteins’ binding site surface is shallow and wide in shape, rendering it difficult for traditional small molecular organic drugs to bind and block its activity, thus destroying the cancer cells. Peptoids are capable of binding to such sites but must be designed to contain optimal residues. Peptoids OP1 and OP2 have been synthesized to bind to the KRAS in multiple target sites, and cytotoxicity assays were used to evaluate these two compounds for their potential as drug-leads. MTS results showed that OP1 has greater cytotoxic activity than OP2, though only at concentrations greater than 50 μM, and that both compounds have cytotoxic effects at high concentrations (approximately 100 μM). Both OP1 and OP2 require further optimization and are candidates for future studies in compound optimization, binding validation, biological activity validation, and mechanistic studies.

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