PMID- 29129745
OWN - NLM
STAT- MEDLINE
DCOM- 20180724
LR  - 20180724
IS  - 1638-6183 (Electronic)
IS  - 0300-9084 (Linking)
VI  - 144
DP  - 2018 Jan
TI  - Fluorescent light-up acridine orange derivatives bind and stabilize KRAS-22RT 
      G-quadruplex.
PG  - 144-152
LID - S0300-9084(17)30284-5 [pii]
LID - 10.1016/j.biochi.2017.11.004 [doi]
AB  - KRAS is often found mutated in lethal cancers and should be an important target 
      for anticancer drug development. However, no effective inhibitor has been 
      reported so far, prompting the scientific community to describe the RAS proteins 
      as nearly "undruggable". Recent approaches developed to modulate KRAS protein 
      expression comprises the targeting of G-quadruplex (G4) structures formed within 
      the nuclease hypersensitive element of KRAS promoter region, by designing small 
      and specific ligands to stabilize the tertiary fold and reduce gene expression. 
      In this work, we report in vitro and in silico studies of novel acridine orange 
      (AO) derivatives (C(3)-C(8)), developed as G4 stabilizing agents. The results 
      show that the ligands bind with high affinity and stabilize KRAS22-RT G4 with 
      modest specificity over duplex DNA. The most promising ligand C(8) stabilizes the 
      structure by  approximately  40  degrees C. Molecular docking using NMR-derived distance restraints 
      reveal atomic details about the ligand structural features in the interaction 
      with KRAS22-RT G4. In vitro studies with HeLa cells show that the ligands are 
      cytotoxic with IC50 values between 0.9 muM and 5.7 muM. Moreover, the ligands tend 
      to localize in the nucleus as shown by confocal fluorescence microscopy. Overall, 
      these results show that the reported AO ligands display favourable properties as 
      G4 ligands and this study provides structural detail for the development of lead 
      KRAS G4 ligands.
CI  - Copyright (c) 2017 Elsevier B.V. and Societe Francaise de Biochimie et Biologie 
      Moleculaire (SFBBM). All rights reserved.
FAU - Carvalho, Josue
AU  - Carvalho J
AD  - CICS-UBI - Centro de Investigacao em Ciencias da Saude, Universidade da Beira 
      Interior, Av. Infante D. Henrique, 6200-506, Covilha, Portugal.
FAU - Pereira, Edgar
AU  - Pereira E
AD  - Centro de Ciencias e Tecnologias Nucleares, Instituto Superior Tecnico, 
      Universidade de Lisboa, Estrada Nacional 10 (km 139,7), 2695-066, Bobadela LRS, 
      Portugal.
FAU - Marquevielle, Julien
AU  - Marquevielle J
AD  - Univ. Bordeaux, ARNA Laboratory, INSERM, U1212, CNRS UMR 5320, IECB, F-33600, 
      Pessac, France.
FAU - Campello, Maria P C
AU  - Campello MPC
AD  - Centro de Ciencias e Tecnologias Nucleares, Instituto Superior Tecnico, 
      Universidade de Lisboa, Estrada Nacional 10 (km 139,7), 2695-066, Bobadela LRS, 
      Portugal.
FAU - Mergny, Jean-Louis
AU  - Mergny JL
AD  - Univ. Bordeaux, ARNA Laboratory, INSERM, U1212, CNRS UMR 5320, IECB, F-33600, 
      Pessac, France; Institute of Biophysics, AS CR, v.v.i. Kralovopolska 135, 612 65, 
      Brno, Czech Republic.
FAU - Paulo, Antonio
AU  - Paulo A
AD  - Centro de Ciencias e Tecnologias Nucleares, Instituto Superior Tecnico, 
      Universidade de Lisboa, Estrada Nacional 10 (km 139,7), 2695-066, Bobadela LRS, 
      Portugal. Electronic address: apaulo@ctn.tecnico.ulisboa.pt.
FAU - Salgado, Gilmar F
AU  - Salgado GF
AD  - Univ. Bordeaux, ARNA Laboratory, INSERM, U1212, CNRS UMR 5320, IECB, F-33600, 
      Pessac, France.
FAU - Queiroz, Joao A
AU  - Queiroz JA
AD  - CICS-UBI - Centro de Investigacao em Ciencias da Saude, Universidade da Beira 
      Interior, Av. Infante D. Henrique, 6200-506, Covilha, Portugal.
FAU - Cruz, Carla
AU  - Cruz C
AD  - CICS-UBI - Centro de Investigacao em Ciencias da Saude, Universidade da Beira 
      Interior, Av. Infante D. Henrique, 6200-506, Covilha, Portugal. Electronic 
      address: carlacruz@fcsaude.ubi.pt.
LA  - eng
PT  - Journal Article
DEP - 20171110
PL  - France
TA  - Biochimie
JT  - Biochimie
JID - 1264604
RN  - 0 (Fluorescent Dyes)
RN  - 0 (KRAS protein, human)
RN  - 0 (Ligands)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
RN  - F30N4O6XVV (Acridine Orange)
SB  - IM
MH  - Acridine Orange/*chemistry/metabolism/*pharmacology
MH  - Biological Transport
MH  - Cell Proliferation/drug effects
MH  - Fluorescent Dyes/*chemistry/metabolism/*pharmacology
MH  - G-Quadruplexes/*drug effects
MH  - HeLa Cells
MH  - Humans
MH  - Intracellular Space/metabolism
MH  - Ligands
MH  - Proto-Oncogene Proteins p21(ras)/*genetics
OTO - NOTNLM
OT  - Acridine orange ligands
OT  - Fluorescent probes
OT  - G-quadruplex
OT  - KRAS promoter
OT  - NMR spectroscopy
EDAT- 2017/11/14 06:00
MHDA- 2018/07/25 06:00
CRDT- 2017/11/14 06:00
PHST- 2017/07/23 00:00 [received]
PHST- 2017/11/06 00:00 [accepted]
PHST- 2017/11/14 06:00 [pubmed]
PHST- 2018/07/25 06:00 [medline]
PHST- 2017/11/14 06:00 [entrez]
AID - S0300-9084(17)30284-5 [pii]
AID - 10.1016/j.biochi.2017.11.004 [doi]
PST - ppublish
SO  - Biochimie. 2018 Jan;144:144-152. doi: 10.1016/j.biochi.2017.11.004. Epub 2017 Nov 
      10.