Discovery of PARP1-Sparing Inhibitors for Protein ADP-Ribosylation

Elisa N Stephens; Liang-Chieh Chen; Arshad J Ansari; Kaiyu Shen; Lei Zhang; Steven G Guillen; Clay C C Wang; Yong Zhang

doi:10.1021/acsmedchemlett.4c00395

Discovery of PARP1-Sparing Inhibitors for Protein ADP-Ribosylation

ACS Med Chem Lett. 2024 Oct 30;15(11):1940-1946. doi: 10.1021/acsmedchemlett.4c00395. eCollection 2024 Nov 14.

Authors

Elisa N Stephens¹, Liang-Chieh Chen¹, Arshad J Ansari¹, Kaiyu Shen¹, Lei Zhang¹, Steven G Guillen², Clay C C Wang^{1

2}, Yong Zhang^{1

2

3

4}

Affiliations

¹ Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, California 90089, United States.
² Department of Chemistry, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California 90089, United States.
³ Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California 90089, United States.
⁴ Research Center for Liver Diseases, University of Southern California, Los Angeles, California 90089, United States.

Abstract

Poly-ADP-ribose polymerases (PARPs) that catalyze cellular ADP-ribosylation play important roles in human health. PARP inhibitors have found success in the clinic for cancer treatment. However, isoform-specific inhibitors are needed for improved safety. Here, we report the unexpected discovery of nicotinamide mimics that block non-PARP1-catalyzed ADP-ribosylation at micromolar concentrations. These PARP1-sparing PARP inhibitors represent first-in-class probes for ADP-ribosylation, shedding light on the selective inhibition of PARPs.

Abstract

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