PARP (poly-ADP-ribose polymerase) family proteins are promising therapeutic targets whose main roles involve maintaining DNA integrity and programmed cell death. PARP-1catalyzes the transfer of ADP-ribose units to a variety of nuclear proteins (histones, transcription factors and PARP itself) using nicotinamide adenine dinucleotide (NAD+) as a substrate. This is a key process for the repair of DNA damage by a pathway known as base excision repair. Thus, blocking PARP’s activity prevents DNA damage repair which finally leads to cell death. Most of the PARP inhibitors developed to date are structural analogues of nicotinamide and are thought to compete with NAD itself at the level of the catalytic domain. In this poster we report the molecular modelling studies, synthesis and biological activity evaluation of 6-substituted pyrrolo[2,3-b]pyridine-1-carboxamides (7-azaindoles) as a new class of PARP-1 inhibitors. In general, the compounds showed a good inhibitory activity against human PARP-1. The most active derivative was selected for further investigation. It showed to be an active inhibitor in a suitable cellular PARylation assay on human endometrial carcinoma HeLa cells. Studies of combination with temozolomide on two human tumor cell lines clearly indicated synergy between the two agents. The selected compound was also investigated in vivo against MX1, a triple-negative human breast tumor carrying BRCA1 deletion and BRCA2 mutation, in comparison with olaparib. Interestingly, it significantly affected tumor growth showing an activity comparable to that of olaparib given at equimolar dose by using the same schedule and route of administration.
|Titolo:||Design, synthesis and antitumor activity evaluation of a new class of PARP-1 inhibitors|
|Data di pubblicazione:||19-set-2013|
|Settore Scientifico Disciplinare:||Settore CHIM/06 - Chimica Organica|
|Citazione:||Design, synthesis and antitumor activity evaluation of a new class of PARP-1 inhibitors / L. Musso, R. Cincinelli, S. Dallavalle, R. Artali, G. Giannini, L. Vesci, F. Milazzo.. ((Intervento presentato al convegno Working Group Meeting of COST Action CM1106 : Chemical Approaches to Targeting Drug Resistance in Cancer Stem Cells tenutosi a Warsaw nel 2013.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|