Selective Targeting of the KRAS Codon12 Mutation Sequence by Pyrrole-Imidazole Polyamide seco-CBI Conjugates

Mutation of KRAS is a key step in many cancers. Mutations occur most frequently at codon12, but the targeting of KRAS is notoriously difficult. We recently demonstrated selective reduction in the volume of tumors harboring the KRAS codon12 mutation in a mouse model by using an alkylating hairpin N-m...

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Published inChemistry : a European journal Vol. 21; no. 42; pp. 14996 - 15003
Main Authors Taylor, Rhys D, Chandran, Anandhakumar, Kashiwazaki, Gengo, Hashiya, Kaori, Bando, Toshikazu, Nagase, Hiroki, Sugiyama, Hiroshi
Format Journal Article
LanguageEnglish
Published Weinheim Wiley Subscription Services, Inc 12.10.2015
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Abstract Mutation of KRAS is a key step in many cancers. Mutations occur most frequently at codon12, but the targeting of KRAS is notoriously difficult. We recently demonstrated selective reduction in the volume of tumors harboring the KRAS codon12 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 codon12 mutation sequence. Herein, we have compared the alkylating activity of 4 against three other conjugates that were also designed to target the KRAS codon12 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.
AbstractList Mutation of KRAS is a key step in many cancers. Mutations occur most frequently at codon12, but the targeting of KRAS is notoriously difficult. We recently demonstrated selective reduction in the volume of tumors harboring the KRAS codon12 mutation in a mouse model by using an alkylating hairpin N-methylpyrrole-N-methylim idazole 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 codon12 mutation sequence. Herein, we have compared the alkylating activity of 4 against three other conjugates that were also designed to target the KRAS codon12 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. Targeted hairpins: N-Methylpyrrole-N-methylim idazole (Py-Im) polyamide seco-CBI (CBI=1,2,9,9a-tetrahydrocyclopropa[1,2-c]benz[1,2-e]indol-4-one) conjugates target the KRAS codon12 mutation with high affinity and specificity. After optimization of the beta -alanine pairings of four Py-Im polyamide conjugates for sequence-specific alkylation, conjugate1 was synthesized for evaluation of Py-Im polyamide sequence specificity for the KRAS codon12 mutation sequence (see figure).
Mutation of KRAS is a key step in many cancers. Mutations occur most frequently at codon12, but the targeting of KRAS is notoriously difficult. We recently demonstrated selective reduction in the volume of tumors harboring the KRAS codon12 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 codon12 mutation sequence. Herein, we have compared the alkylating activity of 4 against three other conjugates that were also designed to target the KRAS codon12 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.
Author Chandran, Anandhakumar
Taylor, Rhys D
Nagase, Hiroki
Kashiwazaki, Gengo
Hashiya, Kaori
Sugiyama, Hiroshi
Bando, Toshikazu
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Snippet Mutation of KRAS is a key step in many cancers. Mutations occur most frequently at codon12, but the targeting of KRAS is notoriously difficult. We recently...
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SubjectTerms Affinity
Alkylation
Cancer
Chemistry
Conjugates
Mutation
Mutations
Optimization
Polyamide resins
Sequencing
Title Selective Targeting of the KRAS Codon12 Mutation Sequence by Pyrrole-Imidazole Polyamide seco-CBI Conjugates
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