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Chemistry. 2015 Oct 12;21(42):14996-5003. doi: 10.1002/chem.201501870. Epub 2015 Aug 26.

Selective Targeting of the KRAS Codon 12 Mutation Sequence by Pyrrole-Imidazole Polyamide seco-CBI Conjugates.

Author information

1
Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-Ku, Kyoto, 606-8502 (Japan).
2
Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-Ku, Kyoto, 606-8502 (Japan). bando@kuchem.kyoto-u.ac.jp.
3
Chiba Cancer Center Research Institute, Chuo-Ku, Chiba, 260-8717 (Japan).
4
Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-Ku, Kyoto, 606-8502 (Japan). hs@kuchem.kyoto-u.ac.jp.
5
Institute for Integrated Cell-Materials Sciences (iCeMS), Kyoto University, Yoshida-ushinomiyacho, Sakyo-Ku, Kyoto, 606-8501 (Japan). hs@kuchem.kyoto-u.ac.jp.
6
CREST (Japan) Science and Technology Corporation (JST), Sanbancho, Chiyoda-Ku, Tokyo, 102-0075 (Japan). hs@kuchem.kyoto-u.ac.jp.

Abstract

Mutation of KRAS is a key step in many cancers. Mutations occur most frequently at codon 12, but the targeting of KRAS is notoriously difficult. We recently demonstrated selective reduction in the volume of tumors harboring the KRAS codon 12 mutation in a mouse model by using an alkylating hairpin N-methylpyrrole-N-methylimidazole polyamide seco-1,2,9,9a-tetrahydrocyclopropa[1,2-c]benz[1,2-e]indol-4-one conjugate (conjugate 4) designed to target the KRAS codon 12 mutation sequence. Herein, we have compared the alkylating activity of 4 against three other conjugates that were also designed to target the KRAS codon 12 mutation sequence. Conjugate 4 displayed greater affinity for the G12D mutation sequence than for the G12V sequence. A computer-minimized model suggested that conjugate 4 could bind more efficiently to the G12D match sequence than to a one-base-pair mismatch sequence. Conjugate 4 was modified for next-generation sequencing. Bind-n-Seq analysis supported the evidence showing that conjugate 4 could target the G12D mutation sequence with exceptionally high affinity and the G12V mutation sequence with much higher affinity than that for the wild-type sequence.

KEYWORDS:

DNA; alkylation; mutations; polyamides; sequence recognition

PMID:
26306751
DOI:
10.1002/chem.201501870

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