Inhibition of KRAS codon 12 mutants using a novel DNA-alkylating pyrrole-imidazole polyamide conjugate

Nat Commun. 2015 Apr 27:6:6706. doi: 10.1038/ncomms7706.

Abstract

Despite extensive efforts to target mutated RAS proteins, anticancer agents capable of selectively killing tumour cells harbouring KRAS mutations have remained unavailable. Here we demonstrate the direct targeting of KRAS mutant DNA using a synthetic alkylating agent (pyrrole-imidazole polyamide indole-seco-CBI conjugate; KR12) that selectively recognizes oncogenic codon 12 KRAS mutations. KR12 alkylates adenine N3 at the target sequence, causing strand cleavage and growth suppression in human colon cancer cells with G12D or G12V mutations, thus inducing senescence and apoptosis. In xenograft models, KR12 infusions induce significant tumour growth suppression, with low host toxicity in KRAS-mutated but not wild-type tumours. This newly developed approach may be applicable to the targeting of other mutant driver oncogenes in human tumours.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects
  • Caco-2 Cells
  • Cellular Senescence / drug effects
  • DNA Damage
  • Drug Evaluation, Preclinical
  • Female
  • HT29 Cells
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / pharmacology
  • Imidazoles / therapeutic use*
  • Mice, Nude
  • Mutation
  • Neoplasms, Experimental / drug therapy*
  • Nylons / chemical synthesis*
  • Nylons / pharmacology
  • Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors*
  • Proto-Oncogene Proteins p21(ras) / genetics

Substances

  • Antineoplastic Agents
  • Imidazoles
  • KR12 compound
  • KRAS protein, human
  • Nylons
  • Proto-Oncogene Proteins p21(ras)