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