Design, Synthesis and Evaluation of Potential Inhibitors for Poly(ADP-Ribose) Polymerase Members 1 and 14

Abstract

Poly(ADP-ribose) polymerase (PARP) members PARP1 and PARP14 belong to an 18-member superfamily of post-translational modifying enzymes. A library of 9 novel non-NAD analog amine compounds was designed, synthesized and evaluated for inhibitory activity against PARP1 and PARP14. Both in silico studies and in vitro assays identified compound 2 as a potential PARP1 inhibitor, inhibiting activity by 93 ± 2% (PARP14 inhibition: 0 ± 6%), and 7 as a potential PARP14 inhibitor, inhibiting activity by 91 ± 2% (PARP1 inhibition: 18 ± 4%), at 10-μm concentration. Key in silico interactions with TYR907 in PARP1 and TYR1620 and TYR1646 in PARP14 have been identified. Compound 2 and compound 7 have been identified as potential leads for the development of selective PARP inhibitors.

Graphical abstract

Keywords: :

• molecular docking
• PARP14
• PARP inhibitors
• PARP1
• reductive amination

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at:www.futurescience.com/doi/suppl/10.4155/fmc-2020-0218

Financial & competing interests disclosure

This work was supported by Bond University, and all financial support has been provided by the university. The authors declare no conflicts of interest. No writing assistance was employed in the production of this manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.