Analogs of TIQ-A as inhibitors of human mono-ADP-ribosylating PARPs
Analogs of TIQ-A as inhibitors of human mono-ADP-ribosylating PARPs
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.
Sowa Sven T.、Galera-Prat Albert、Heiskanen Juha P.、Lehti? Lari、Maksimainen Mirko M.、Rolina Elena、Murthy Sudarshan
Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of OuluFaculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of OuluResearch Unit of Sustainable Chemistry, Faculty of Technology, University of OuluFaculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of OuluFaculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of OuluFaculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of OuluFaculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu
药学生物科学研究方法、生物科学研究技术生物化学
TIQ-AADP-ribosylationADP-ribosyltransferasePARPstructure-guided inhibitor design
Sowa Sven T.,Galera-Prat Albert,Heiskanen Juha P.,Lehti? Lari,Maksimainen Mirko M.,Rolina Elena,Murthy Sudarshan.Analogs of TIQ-A as inhibitors of human mono-ADP-ribosylating PARPs[EB/OL].(2025-03-28)[2025-04-30].https://www.biorxiv.org/content/10.1101/2021.08.30.458193.点此复制
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