title: Concepts and Molecular Aspects in the Polypharmacology of PARP-1 Inhibitors.
abstract: Recent years have witnessed a renewed interest in PARP-1 inhibitors as promising anticancer agents with multifaceted functions. Particularly exciting developments include the approval of olaparib (Lynparza) for the treatment of refractory ovarian cancer in patients with BRCA1/2 mutations, and the increasing understanding of the polypharmacology of PARP-1 inhibitors. The aim of this review article is to provide the reader with a comprehensive overview of the distinct levels of the polypharmacology of PARP-1 inhibitors, including 1) inter-family polypharmacology, 2) intra-family polypharmacology, and 3) multi-signaling polypharmacology. Progress made in gaining insight into the molecular basis of these multiple target-independent and target-dependent activities of PARP-1 inhibitors are discussed, with an outlook on the potential impact that a better understanding of polypharmacology may have in aiding the explanation as to why some drug candidates work better than others in clinical settings, albeit acting on the same target with similar inhibitory potency.
authors.affiliation: TES Pharma S.r.l., via Palmiro Togliatti 20, 06073 Corciano, Perugia, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Passeri
authors.affiliation: Dipartimento di Scienze Farmaceutiche, University of Perugia, Via del Liceo 1, 06123, Perugia, Italy.
authors.forename: Emidio
authors.initials: E
authors.lastname: Camaioni
authors.affiliation: TES Pharma S.r.l., via Palmiro Togliatti 20, 06073 Corciano, Perugia, Italy.
authors.forename: Paride
authors.initials: P
authors.lastname: Liscio
authors.affiliation: TES Pharma S.r.l., via Palmiro Togliatti 20, 06073 Corciano, Perugia, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Sabbatini
authors.affiliation: Dipartimento di Scienze Farmaceutiche, University of Perugia, Via del Liceo 1, 06123, Perugia, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Ferri
authors.affiliation: Dipartimento di Scienze Farmaceutiche, University of Perugia, Via del Liceo 1, 06123, Perugia, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Carotti
authors.affiliation: TES Pharma S.r.l., via Palmiro Togliatti 20, 06073 Corciano, Perugia, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Giacchè
authors.affiliation: TES Pharma S.r.l., via Palmiro Togliatti 20, 06073 Corciano, Perugia, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pellicciari
authors.affiliation: Dipartimento di Scienze Farmaceutiche, University of Perugia, Via del Liceo 1, 06123, Perugia, Italy.
authors.forename: Antimo
authors.initials: A
authors.lastname: Gioiello
authors.affiliation: Dipartimento di Scienze Farmaceutiche, University of Perugia, Via del Liceo 1, 06123, Perugia, Italy. antonio.macchiarulo@unipg.it.
authors.forename: Antonio
authors.identifier: http://orcid.org/0000-0001-9535-4183
authors.initials: A
authors.lastname: Macchiarulo
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D001665:Binding Sites; D005260:Female; D006801:Humans; D056004:Molecular Dynamics Simulation; D010051:Ovarian Neoplasms / Q000188:drug therapy; D010793:Phthalazines / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D064798:Polypharmacology; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000071137:Poly (ADP-Ribose) Polymerase-1; D011494:Protein Kinases; C531550:olaparib
keywords: PARP-1 inhibitors; cancer; drug discovery; ischemia; polypharmacology