title: KRAS oncogene repression in colon cancer cell lines by G-quadruplex binding indolo[3,2-c]quinolines.
abstract: KRAS is one of the most frequently mutated oncogenes in human cancer, yet remaining undruggable. To explore a new therapeutic strategy, a library of 5-methyl-indolo[3,2-c]quinoline derivatives (IQc) with a range of alkyldiamine side chains was designed to target DNA and RNA G-quadruplexes (G4) in the promoter and 5'-UTR mRNA of the KRAS gene. Biophysical experiments showed that di-substituted IQc compounds are potent and selective KRAS G4 stabilizers. They preferentially inhibit the proliferation of KRAS mutant cancer cell lines (0.22 < IC50 < 4.80 μM), down-regulate KRAS promoter activity in a luciferase reporter assay, and reduce both KRAS mRNA and p21(KRAS) steady-state levels in mutant KRAS colon cancer cell lines. Additionally, IQcs induce cancer cell death by apoptosis, explained in part by their capacity to repress KRAS expression. Overall, the results suggest that targeting mutant KRAS at the gene level with G4 binding small molecules is a promising anticancer strategy.
authors: Medicinal Chemistry Group, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
authors: João
authors: J
authors: Lavrado
authors: Cell Function and Therapeutic Targeting Group, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
authors: Hugo
authors: H
authors: Brito
authors: Cell Function and Therapeutic Targeting Group, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
authors: Pedro M
authors: PM
authors: Borralho
authors: The School of Pharmacy, University College London. 29/39 Brunswick Square, London WC1N 1AX, United Kingdom.
authors: Stephan A
authors: SA
authors: Ohnmacht
authors: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-333, Republic of Korea.
authors: Nam-Soon
authors: NS
authors: Kim
authors: The School of Pharmacy, University College London. 29/39 Brunswick Square, London WC1N 1AX, United Kingdom.
authors: Clara
authors: C
authors: Leitão
authors: The School of Pharmacy, University College London. 29/39 Brunswick Square, London WC1N 1AX, United Kingdom.
authors: Sílvia
authors: S
authors: Pisco
authors: The School of Pharmacy, University College London. 29/39 Brunswick Square, London WC1N 1AX, United Kingdom.
authors: Mekala
authors: M
authors: Gunaratnam
authors: Cell Function and Therapeutic Targeting Group, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
authors: Cecília M P
authors: CM
authors: Rodrigues
authors: Medicinal Chemistry Group, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
authors: Rui
authors: R
authors: Moreira
authors: The School of Pharmacy, University College London. 29/39 Brunswick Square, London WC1N 1AX, United Kingdom.
authors: Stephen
authors: S
authors: Neidle
authors: Medicinal Chemistry Group, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
authors: Alexandra
authors: A
authors: Paulo
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004355:Drug Stability; D054856:G-Quadruplexes; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D011905:Genes, ras; D006801:Humans; D007211:Indoles / Q000737:chemistry; D015394:Molecular Structure; D011401:Promoter Regions, Genetic; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011804:Quinolines