Related Experiment Video
Updated: Apr 5, 2026
Biotinylated Cell-penetrating Peptides to Study Intracellular Protein-protein Interactions
Published on: December 20, 2017
Selective Targeting of the KRAS Codon 12 Mutation Sequence by Pyrrole-Imidazole Polyamide seco-CBI Conjugates
Rhys D Taylor1, Anandhakumar Chandran1, Gengo Kashiwazaki1
1Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-Ku, Kyoto, 606-8502 (Japan).
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.
Insights
A novel conjugate effectively targets KRAS codon 12 mutations, showing high affinity for G12D and G12V variants. This offers a promising strategy for developing new cancer therapies.
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- KRAS mutations are crucial drivers in numerous cancers.
- Targeting KRAS mutations, particularly at codon 12, presents significant therapeutic challenges.
Purpose of the Study:
- To compare the alkylating activity of conjugate 4 with other KRAS codon 12-targeting conjugates.
- To evaluate the binding affinity and specificity of conjugate 4 for KRAS G12D and G12V mutations.
Main Methods:
- Synthesis and evaluation of alkylating hairpin polyamide conjugates.
- Computer-minimized modeling to predict binding efficiency.
- Bind-n-Seq analysis to assess sequence-specific DNA binding affinity.
Main Results:
- Conjugate 4 demonstrated higher affinity for the KRAS G12D mutation sequence compared to the G12V sequence.
- Computational modeling indicated superior binding of conjugate 4 to the G12D sequence over mismatched sequences.
- Bind-n-Seq confirmed high affinity for G12D and significantly enhanced affinity for G12V over wild-type KRAS sequences.
Conclusions:
- Conjugate 4 exhibits potent and specific targeting of KRAS codon 12 mutations, particularly G12D.
- The findings support the development of conjugate 4 as a potential therapeutic agent for KRAS-mutated cancers.
More Related Videos
10:13A Multiplexed Luciferase-based Screening Platform for Interrogating Cancer-associated Signal Transduction in Cultured Cells
Published on: July 3, 2013
06:51Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
Published on: July 21, 2018
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...