Abstract
Poly ADP-ribose polymerases (PARP) are key proteins involved in DNA repair, maintenance as well as regulation of programmed cell death. For this reason they are important therapeutic targets for cancer treatment. Recent studies have revealed a close interplay between PARP1 recruitment and G-quadruplex stabilization, showing that PARP enzymes are activated upon treatment with a G4 ligand. In this work the DNA binding properties of a PARP-1 inhibitor derived from 7-azaindole-1-carboxamide, (2-[6-(4-pyrrolidin-1-ylmethyl-phenyl)-pyrrolo[2,3-b]pyridin-1-yl]-acetamide, compound 1) with model duplex and quadruplex DNA oligomers were studied by NMR, CD, fluorescence and molecular modelling. We provide evidence that compound 1 is a strong G-quadruplex binder. In addition we provide molecular details of the interaction of compound 1 with two model G-quadruplex structures: the single repeat of human telomeres, d(TTAGGGT)4, and the c-MYC promoter Pu22 sequence. The formation of defined and strong complexes with G-quadruplex models suggests a dual G4 stabilization/PARP inhibition mechanism of action for compound 1 and provides the molecular bases of its therapeutic potential.
Highlights
Cancer remains a leading cause of death worldwide
In this paper we report a fluorescence, CD, NMR and molecular modelling study focused on the interaction of 1 with the single repeat sequence of human telomeres, d(TTAGGGT)[423], and with the G-quadruplex found in the c-MYC promoter Pu22 sequence, whose overexpression is one of the most common aberration in a wide range of human tumors
Spectra of both the self-complementary oligonucleotides d(CGTACG)[2] (“CG”) and d(AAGAATTCTT)[2] (“AATT”) display signals in a region ranging from 12 to-13.5 ppm, which are characteristic of the NH imino protons of CG and AT base pairs
Summary
Cancer remains a leading cause of death worldwide. A majority of anticancer drugs induce cell death through DNA binding and damage. Advances in the molecular biology of cancer have identified key mechanisms involved in DNA repair induced by chemotherapeutic drugs indicating that cancer cells overexpress DNA repair pathways as mechanisms of drug r esistance[1]. Blocking these pathways has emerged as an attractive approach for cancer therapy[2]. The superfamily of PARPs consists of six different enzymes: PARP-1, PARP-2, PARP-3, PARP-4/VPARP, tankyrase-1 and tankyrase-2 These enzymes are involved in various cellular functions, including cell cycle regulation, transcription, and DNA damage repair. Their structural building block is the G-quartet, a planar array of 4
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