title: Selective Targeting of the KRAS Codon 12 Mutation Sequence by Pyrrole-Imidazole Polyamide seco-CBI Conjugates.
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.
authors: Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-Ku, Kyoto, 606-8502 (Japan).
authors: Rhys D
authors: RD
authors: Taylor
authors: Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-Ku, Kyoto, 606-8502 (Japan).
authors: Anandhakumar
authors: A
authors: Chandran
authors: Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-Ku, Kyoto, 606-8502 (Japan).
authors: Gengo
authors: G
authors: Kashiwazaki
authors: Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-Ku, Kyoto, 606-8502 (Japan).
authors: Kaori
authors: K
authors: Hashiya
authors: Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-Ku, Kyoto, 606-8502 (Japan). bando@kuchem.kyoto-u.ac.jp.
authors: Toshikazu
authors: T
authors: Bando
authors: Chiba Cancer Center Research Institute, Chuo-Ku, Chiba, 260-8717 (Japan).
authors: Hiroki
authors: H
authors: Nagase
authors: Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-Ku, Kyoto, 606-8502 (Japan). hs@kuchem.kyoto-u.ac.jp.|Institute for Integrated Cell-Materials Sciences (iCeMS), Kyoto University, Yoshida-ushinomiyacho, Sakyo-Ku, Kyoto, 606-8501 (Japan). hs@kuchem.kyoto-u.ac.jp.|CREST (Japan) Science and Technology Corporation (JST), Sanbancho, Chiyoda-Ku, Tokyo, 102-0075 (Japan). hs@kuchem.kyoto-u.ac.jp.
authors: Hiroshi
authors: H
authors: Sugiyama
keywords: DNA; alkylation; mutations; polyamides; sequence recognition