Abstract
EGFR is an oncogene that encodes for a trans-membrane tyrosine kinase receptor. Its mis-regulation is associated to several human cancers that, consistently, can be treated by selective tyrosine kinase inhibitors. The proximal promoter of EGFR contains a G-rich domain located at 272 bases upstream the transcription start site. We previously proved it folds into two main interchanging G-quadruplex structures, one of parallel and one of hybrid topology. Here we present the first evidences supporting the ability of the complementary C-rich strand (EGFR-272_C) to assume an intramolecular i-Motif (iM) structure that, according to the experimental conditions (pH, presence of co-solvent and salts), can coexist with a different arrangement we referred to as a hairpin. The herein identified iM efficiently competes with the canonical pairing of the two complementary strands, indicating it as a potential novel target for anticancer therapies. A preliminary screening for potential binders identified some phenanthroline derivatives as able to target EGFR-272_C at multiple binding sites when it is folded into an iM.
Highlights
A strategy to overcome these drawbacks lies in impairing the production of the protein
Among the various non-canonical structures adopted by nucleic acids, large attention has been given to tetra-helices such as G-quadruplex (G4) and i-Motif, formed by guanine-rich and cytosine-rich sequences, respectively
We showed that EGFR promoter contains a G-rich sequence located 272 bases upstream the transcription start site (EGFR-272, 56.6% of guanines) that is able to fold into G426
Summary
A strategy to overcome these drawbacks lies in impairing the production of the protein. Among the various non-canonical structures adopted by nucleic acids, large attention has been given to tetra-helices such as G-quadruplex (G4) and i-Motif (iM), formed by guanine-rich and cytosine-rich sequences, respectively As far it concerns G4, four strands of variable polarity are held together by co-planar pairing of four guanines to generate G-tetrads that stack one over the other[15]. We present the first evidences supporting the ability of this C-rich sequence (EGFR-272_C) to assume an iM structure We showed that this tetra-helical conformation is significantly stable but, according to the experimental conditions (pH, presence of cosolvent or salts and small molecules) it can be converted into an intramolecular arrangement likely referring to a hairpin. We confirmed that a single Phen unit is sufficient to obtain derivatives able to remarkably increase the stability of the iM folding of EGFR-272_C
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