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. Epub 2021 Nov 10.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP Ribose Transferases / antagonists & inhibitors*
  • ADP Ribose Transferases / metabolism
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Humans
  • Isoquinolines / chemical synthesis
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Poly(ADP-ribose) Polymerase Inhibitors / chemical synthesis
  • Poly(ADP-ribose) Polymerase Inhibitors / chemistry
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / metabolism
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*


  • Isoquinolines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Proto-Oncogene Proteins
  • Thiophenes
  • thieno(2,3-c)isoquinolin-5-one
  • ADP Ribose Transferases
  • PARP15 protein, human
  • PARP10 protein, human
  • Poly(ADP-ribose) Polymerases