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• W2062852255 abstract "Despite extensive efforts to target mutated RAS proteins, anticancer agents capable of selectively killing tumour cells harbouring KRAS mutations have remained unavailable. Here we demonstrate the direct targeting of KRAS mutant DNA using a synthetic alkylating agent (pyrrole–imidazole polyamide indole-seco-CBI conjugate; KR12) that selectively recognizes oncogenic codon 12 KRAS mutations. KR12 alkylates adenine N3 at the target sequence, causing strand cleavage and growth suppression in human colon cancer cells with G12D or G12V mutations, thus inducing senescence and apoptosis. In xenograft models, KR12 infusions induce significant tumour growth suppression, with low host toxicity in KRAS-mutated but not wild-type tumours. This newly developed approach may be applicable to the targeting of other mutant driver oncogenes in human tumours. RAS, identified over 30 years ago as a potent oncogene, is one of the most commonly mutated genes in cancer. Here the authors show that KR12, an alkylating reagent that specifically cleaves the DNA coding for the G12D and G12V activated variants of KRAS, limits the growth of KRAS mutant cells in vitro and in vivo." @default.
• W2062852255 created "2016-06-24" @default.
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• W2062852255 date "2015-04-27" @default.
• W2062852255 modified "2023-10-11" @default.
• W2062852255 title "Inhibition of KRAS codon 12 mutants using a novel DNA-alkylating pyrrole–imidazole polyamide conjugate" @default.
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• W2062852255 doi "https://doi.org/10.1038/ncomms7706" @default.
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