2. Academic Validation
  3. Analogs of TIQ-A as inhibitors of human mono-ADP-ribosylating PARPs

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

  • Bioorg Med Chem. 2021 Dec 15;52:116511. doi: 10.1016/j.bmc.2021.116511.
Mirko M Maksimainen 1,  Sudarshan Murthy 1,  Sven T Sowa 1,  Albert Galera-Prat 1,  Elena Rolina 1,  Juha P Heiskanen 2,  Lari Lehtiö 3
Affiliations

Affiliations

  • 1 Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Oulu, Finland.
  • 2 Research Unit of Sustainable Chemistry, Faculty of Technology, University of Oulu, Oulu, Finland.
  • 3 Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Oulu, Finland. Electronic address: lari.lehtio@oulu.fi.
PMID: 34801828 DOI: 10.1016/j.bmc.2021.116511
Abstract

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.

Keywords

ADP-ribosylation; ADP-ribosyltransferase; PARP; Structure-guided inhibitor design; TIQ-A.

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