Catalytic poly(ADP-ribose) production by PARP1 is allosterically activated through interaction with DNA breaks, and PARP inhibitor compounds have the potential to influence PARP1 allostery in addition to preventing catalytic activity. Using the benzimidazole-4-carboxamide pharmacophore present in the first generation PARP1 inhibitor veliparib, a series of 11 derivatives was designed, synthesized, and evaluated as allosteric PARP1 inhibitors, with the premise that bulky substituents would engage the regulatory helical domain (HD) and thereby promote PARP1 retention on DNA breaks. We found that core scaffold modifications could indeed increase PARP1 affinity for DNA; however, the bulk of the modification alone was insufficient to trigger PARP1 allosteric retention on DNA breaks. Rather, compounds eliciting PARP1 retention on DNA breaks were found to be rigidly held in a position that interferes with a specific region of the HD domain, a region that is not targeted by current clinical PARP inhibitors. Collectively, these compounds highlight a unique way to trigger PARP1 retention on DNA breaks and open a path to unveil the pharmacological benefits of such inhibitors with novel properties.
-
Cover Image
Cover Image
In this issue Velagapudi and colleagues (pp. 437–460) highlight a unique way to trigger PARP1 retention on DNA breaks and open a path to unveil the pharmacological benefits of such inhibitors with novel properties. The cover image shows Type I inhibitors modulating PARP1 allostery via different binding poses. The image is courtesy of Tanaji T. Talele.
Novel modifications of PARP inhibitor veliparib increase PARP1 binding to DNA breaks
Uday Kiran Velagapudi, Élise Rouleau-Turcotte, Ramya Billur, Xuwei Shao, Manisha Patil, Ben E. Black, John M. Pascal, Tanaji T. Talele; Novel modifications of PARP inhibitor veliparib increase PARP1 binding to DNA breaks. Biochem J 20 March 2024; 481 (6): 437–460. doi: https://doi.org/10.1042/BCJ20230406
Download citation file:
Sign in
Sign in to your personal account
Biochemical Society Member Sign in
Sign InSign in via your Institution
Sign in via your InstitutionGet Access To This Article
Cited By
Follow us on Twitter @Biochem_Journal
Open Access for all
We offer compliant routes for all authors from 2025. With library support, there will be no author nor reader charges in 5 journals. Check here |
![]() View past webinars > |