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タイトル: | Selective Targeting of the KRAS Codon 12 Mutation Sequence by Pyrrole-Imidazole Polyamide seco-CBI Conjugates. |
著者: | Taylor, Rhys D Chandran, Anandhakumar Kashiwazaki, Gengo Hashiya, Kaori Bando, Toshikazu Nagase, Hiroki Sugiyama, Hiroshi https://orcid.org/0000-0001-8923-5946 (unconfirmed) |
著者名の別形: | 杉山, 弘 |
キーワード: | alkylation DNA mutations sequence recognition polyamides |
発行日: | 12-Oct-2015 |
出版者: | wiley |
誌名: | Chemistry - A European Journal |
巻: | 21 |
号: | 42 |
開始ページ: | 14996 |
終了ページ: | 15003 |
抄録: | 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. |
著作権等: | This is the accepted version of the following article: [Taylor, R. D., Chandran, A., Kashiwazaki, G., Hashiya, K., Bando, T., Nagase, H. and Sugiyama, H. (2015), Selective Targeting of the KRAS Codon 12 Mutation Sequence by Pyrrole–Imidazole Polyamide seco-CBI Conjugates. Chem. Eur. J., 21: 14996–15003], which has been published in final form at http://dx.doi.org/10.1002/chem.201501870. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. The full-text file will be made open to the public on 2 October 2016 in accordance with publisher's 'Terms and Conditions for Self-Archiving'. この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。 This is not the published version. Please cite only the published version. |
URI: | http://hdl.handle.net/2433/207677 |
DOI(出版社版): | 10.1002/chem.201501870 |
PubMed ID: | 26306751 |
出現コレクション: | 学術雑誌掲載論文等 |
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