Analogs of TIQ-A as inhibitors of human mono-ADP-ribosylating PARPs
Maksimainen, Mirko M.; Murthy, Sudarshan; Sowa, Sven T.; Galera-Prat, Albert; Rolina, Elena; Heiskanen, Juha P.; Lehtiö, Lari (2021-11-10)
Mirko M. Maksimainen, Sudarshan Murthy, Sven T. Sowa, Albert Galera-Prat, Elena Rolina, Juha P. Heiskanen, Lari Lehtiö, Analogs of TIQ-A as inhibitors of human mono-ADP-ribosylating PARPs, Bioorganic & Medicinal Chemistry, Volume 52, 2021, 116511, ISSN 0968-0896, https://doi.org/10.1016/j.bmc.2021.116511
© 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
https://creativecommons.org/licenses/by/4.0/
https://urn.fi/URN:NBN:fi-fe2021122061784
Tiivistelmä
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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