University of Oulu

Mirko M. Maksimainen, Sudarshan Murthy, Sven T. Sowa, Albert Galera-Prat, Elena Rolina, Juha P. Heiskanen, Lari Lehtiö, Analogs of TIQ-A as inhibitors of human mono-ADP-ribosylating PARPs, Bioorganic & Medicinal Chemistry, Volume 52, 2021, 116511, ISSN 0968-0896,

Analogs of TIQ-A as inhibitors of human mono-ADP-ribosylating PARPs

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Author: Maksimainen, Mirko M.1; Murthy, Sudarshan1; Sowa, Sven T.1;
Organizations: 1Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Oulu, Finland
2Research Unit of Sustainable Chemistry, Faculty of Technology, University of Oulu, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.4 MB)
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Language: English
Published: Elsevier, 2021
Publish Date: 2021-12-20


The scaffold of TIQ-A, a previously known inhibitor of human poly-ADP-ribosyltransferase PARP1, was utilized to develop inhibitors against human mono-ADP-ribosyltransferases through structure-guided design and activity profiling. By supplementing the TIQ-A scaffold with small structural changes, based on a PARP10 inhibitor OUL35, selectivity changed from poly-ADP-ribosyltransferases towards mono-ADP-ribosyltransferases. Binding modes of analogs were experimentally verified by determining complex crystal structures with mono-ADP-ribosyltransferase PARP15 and with poly-ADP-ribosyltransferase TNKS2. The best analogs of the study achieved 10–20-fold selectivity towards mono-ADP-ribosyltransferases PARP10 and PARP15 while maintaining micromolar potencies. The work demonstrates a route to differentiate compound selectivity between mono- and poly-ribosyltransferases of the human ARTD family.

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Series: Bioorganic & medicinal chemistry
ISSN: 0968-0896
ISSN-E: 1464-3391
ISSN-L: 0968-0896
Volume: 52
Article number: 116511
DOI: 10.1016/j.bmc.2021.116511
Type of Publication: A1 Journal article – refereed
Field of Science: 116 Chemical sciences
1182 Biochemistry, cell and molecular biology
Funding: This work was supported by the Academy of Finland (grant nos. 287063 and 294085 for LL), by Jane and Aatos Erkko foundation (for LL), by Sigrid Jusélius foundation (for LL), by Magnus Ehrnrooth foundation (for SM) and by the Emil Aaltonen foundation (for MMM).
Copyright information: © 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (