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bioRxiv · 10.1101/2021.08.30.458193

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

Maksimainen, M. M.·Murthy, S.·Sowa, S. T.·Galera-Prat, A.·Rolina, E.·Heiskanen, J. P.·Lehtiö, L.
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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.

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Maksimainen, M. M., Murthy, S., Sowa, S. T., Galera-Prat, A., Rolina, E., Heiskanen, J. P., Lehtiö, L.. 2021-08-31. Analogs of TIQ-A as inhibitors of human mono-ADP-ribosylating PARPs. https://doi.org/10.1101/2021.08.30.458193

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