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

Mirko M. Maksimainen; Sudarshan Murthy; Sven T. Sowa; Albert Galera-Prat; Elena Rolina; Juha P. Heiskanen; Lari Lehtiö

doi:10.1016/j.bmc.2021.116511

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

Mirko M. Maksimainen
, Sudarshan Murthy
, Sven T. Sowa
, Albert Galera-Prat
, Elena Rolina
, Juha P. Heiskanen
, Lari Lehtiö^*

^*Corresponding author for this work

Not published at VTT

University of Oulu

Research output: Contribution to journal › Article › Scientific › peer-review

10 Citations (Scopus)

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.

Original language	English
Article number	116511
Journal	Bioorganic and Medicinal Chemistry
Volume	52
DOIs	https://doi.org/10.1016/j.bmc.2021.116511
Publication status	Published - 15 Dec 2021
MoE publication type	A1 Journal article-refereed

Keywords

ADP-ribosylation
ADP-ribosyltransferase
PARP
Structure-guided inhibitor design
TIQ-A

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@article{4d5d5847cc6f4107b98e70f2092092ef,

title = "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.",

keywords = "ADP-ribosylation, ADP-ribosyltransferase, PARP, Structure-guided inhibitor design, TIQ-A",

author = "Maksimainen, \{Mirko M.\} and Sudarshan Murthy and Sowa, \{Sven T.\} and Albert Galera-Prat and Elena Rolina and Heiskanen, \{Juha P.\} and Lari Lehti{\"o}",

year = "2021",

month = dec,

day = "15",

doi = "10.1016/j.bmc.2021.116511",

language = "English",

volume = "52",

journal = "Bioorganic and Medicinal Chemistry",

issn = "0968-0896",

publisher = "Elsevier",

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TY - JOUR

T1 - Analogs of TIQ-A as inhibitors of human mono-ADP-ribosylating PARPs

AU - Maksimainen, Mirko M.

AU - Murthy, Sudarshan

AU - Sowa, Sven T.

AU - Galera-Prat, Albert

AU - Rolina, Elena

AU - Heiskanen, Juha P.

AU - Lehtiö, Lari

PY - 2021/12/15

Y1 - 2021/12/15

N2 - 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.

AB - 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.

KW - ADP-ribosylation

KW - ADP-ribosyltransferase

KW - PARP

KW - Structure-guided inhibitor design

KW - TIQ-A

UR - https://www.scopus.com/pages/publications/85119252105

U2 - 10.1016/j.bmc.2021.116511

DO - 10.1016/j.bmc.2021.116511

M3 - Article

C2 - 34801828

AN - SCOPUS:85119252105

SN - 0968-0896

VL - 52

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

M1 - 116511

ER -

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

Abstract

Keywords

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