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Potent 2,3-dihydrophthalazine-1,4-dione derivatives as dual inhibitors for mono-ADP-ribosyltransferases PARP10 and PARP15

DOI: 10.1016/j.ejmech.2022.114362 DOI Help

Authors: Maria Giulia Nizi (University of Perugia) , Mirko M. Maksimainen (University of Oulu) , Sudarshan Murthy (University of Oulu) , Serena Massari (University of Perugia) , Juho Alaviuhkola (University of Oulu) , Barbara E. Lippok (RWTH Aachen University) , Sven T. Sowa (University of Oulu) , Albert Galera-Prat (University of Oulu) , Renata Prunskaite-Hyyryläinen (University of Oulu) , Bernhard Lüscher (RWTH Aachen University) , Patricia Korn (RWTH Aachen University) , Lari Lehtio (University of Oulu) , Oriana Tabarrini (University of Perugia)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: European Journal Of Medicinal Chemistry , VOL 237

State: Published (Approved)
Published: July 2022
Diamond Proposal Number(s): 19951

Abstract: While human poly-ADP-ribose chain generating poly-ARTs, PARP1 and 2 and TNKS1 and 2, have been widely characterized, less is known on the pathophysiological roles of the mono-ADP-ribosylating mono-ARTs, partly due to the lack of selective inhibitors. In this context, we have focused on the development of inhibitors for the mono-ART PARP10, whose overexpression is known to induce cell death. Starting from OUL35 (1) and its 4-(benzyloxy)benzamidic derivative (2) we herein report the design and synthesis of new analogues from which the cyclobutyl derivative 3c rescued cells most efficiently from PARP10 induced apoptosis. Most importantly, we also identified 2,3-dihydrophthalazine-1,4-dione as a new suitable nicotinamide mimicking PARP10 inhibitor scaffold. When it was functionalized with cycloalkyl (8a-c), o-fluorophenyl (8h), and thiophene (8l) rings, IC50 values in the 130–160 nM range were obtained, making them the most potent PARP10 inhibitors reported to date. These compounds also inhibited PARP15 with low micromolar IC50s, but none of the other tested poly- and mono-ARTs, thus emerging as dual mono-ART inhibitors. Compounds 8a, 8h and 8l were also able to enter cells and rescue cells from apoptosis. Our work sheds more light on inhibitor development against mono-ARTs and identifies chemical probes to study the cellular roles of PARP10 and PARP15.

Journal Keywords: PARP10; PARP15; ADP-Ribosyltransferases; Mono-ARTDs; 2,3-Dihydrophthalazine-1,4-dione; Selective inhibitors; Chemical probes

Subject Areas: Biology and Bio-materials, Medicine, Chemistry

Instruments: I03-Macromolecular Crystallography

Added On: 11/05/2022 11:11

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)