RNF146 Inhibitors

Inhibitors of RNF146, as a conceptual class, would include molecules that interfere with its ability to recognize, bind, or ubiquitinate its PARylated substrates. Since RNF146 is a PAR-dependent E3 ubiquitin ligase, PARP inhibitors can reduce the availability of PARylated proteins, indirectly affecting RNF146's activity. These PARP inhibitors, such as olaparib, veliparib, rucaparib, and others, act by binding to the catalytic site of PARP enzymes, preventing the formation of PAR chains that RNF146 recognizes for ubiquitination. This results in less substrate for RNF146 to target, thus inhibiting its activity indirectly.

The chemical entities that could potentially modulate RNF146 are mostly made up of PARP inhibitors. These inhibitors are diverse in structure but share a common mechanism of action in inhibiting PARP enzymes, which in turn can affect RNF146 activity. Tankyrase inhibitors like XAV-939 also reduce PAR levels but through a different mechanism, targeting tankyrase enzymes rather than PARP. Wnt pathway inhibitors like IWR-1 do not directly inhibit RNF146, but they may reduce the number of proteins that RNF146 would normally ubiquitinate in the Wnt signaling pathway. These inhibitors demonstrate the indirect strategies by which RNF146 activity can be modulated, primarily through the manipulation of protein PARylation status.