University of Oulu

Murthy, S., Nizi, M. G., Maksimainen, M. M., Massari, S., Alaviuhkola, J., Lippok, B. E., Vagaggini, C., Sowa, S. T., Galera-Prat, A., Ashok, Y., Venkannagari, H., Prunskaite-Hyyryläinen, R., Dreassi, E., Lüscher, B., Korn, P., Tabarrini, O., & Lehtiö, L. (2023). [1,2,4]triazolo[3,4- b ]benzothiazole scaffold as versatile nicotinamide mimic allowing nanomolar inhibition of different parp enzymes. Journal of Medicinal Chemistry, 66(2), 1301–1320.

[1,2,4]Triazolo[3,4-b]benzothiazole scaffold as versatile nicotinamide mimic allowing nanomolar inhibition of different PARP enzymes

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Author: Murthy, Sudarshan1; Nizi, Maria Giulia2; Maksimainen, Mirko M.1;
Organizations: 1Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu90220, Finland
2Department of Pharmaceutical Sciences, University of Perugia, Perugia06123, Italy
3Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Aachen52074, Germany
4Department of Biotechnology, Chemistry and Pharmacy, University of Siena, SienaI-53100, Italy
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 5.9 MB)
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Language: English
Published: American Chemical Society, 2023
Publish Date: 2023-03-22


We report [1,2,4]triazolo[3,4-b]benzothiazole (TBT) as a new inhibitor scaffold, which competes with nicotinamide in the binding pocket of human poly- and mono-ADP-ribosylating enzymes. The binding mode was studied through analogues and cocrystal structures with TNKS2, PARP2, PARP14, and PARP15. Based on the substitution pattern, we were able to identify 3-amino derivatives 21 (OUL243) and 27 (OUL232) as inhibitors of mono-ARTs PARP7, PARP10, PARP11, PARP12, PARP14, and PARP15 at nM potencies, with 27 being the most potent PARP10 inhibitor described to date (IC50 of 7.8 nM) and the first PARP12 inhibitor ever reported. On the contrary, hydroxy derivative 16 (OUL245) inhibits poly-ARTs with a selectivity toward PARP2. The scaffold does not possess inherent cell toxicity, and the inhibitors can enter cells and engage with the target protein. This, together with favorable ADME properties, demonstrates the potential of TBT scaffold for future drug development efforts toward selective inhibitors against specific enzymes.

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Series: Journal of medicinal chemistry
ISSN: 0022-2623
ISSN-E: 1520-4804
ISSN-L: 0022-2623
Volume: 66
Issue: 2
Pages: 1301 - 1320
DOI: 10.1021/acs.jmedchem.2c01460
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Funding: The work was supported by the Deutsche Forschungsgemeinschaft funding to BL (Lu 466/16-2), by the Magnus Ehrnrooth Foundation to S.M., and by the Academy of Finland (grant nos. 287063 and 294085) and by Sigrid Jusélius and Jane and Aatos Erkko foundations to L.L.
Academy of Finland Grant Number: 287063
Detailed Information: 287063 (Academy of Finland Funding decision)
294085 (Academy of Finland Funding decision)
Dataset Reference: PDB ID codes: atomic coordinates and structure factors have been deposited to the Protein Data Bank under accession numbers also mentioned in the tables 7R3Z, 7R3L, 7R3O, 7R4A, 7R5X, 7R5D, 7Z1W, 7Z1Y, 7R59, 7Z1V, 7Z41, 7Z2O and 7Z2Q. Raw diffraction images are available at IDA ( Authors will release the atomic coordinates and experimental data upon article publication.
Copyright information: © 2023 The Authors. This is an open access article under the CC BY license (