Poly (ADP-ribose) polymerase family (PARP) (PARP)

The Poly (ADP-ribose) polymerase (PARP) family comprises 17 distinct enzymes that facilitate the transfer of ADP-ribose from NAD+ to target proteins, a process known as ADP-ribosylation (Luo & Kraus, 2012). While PARP1 and PARP2 are well-characterized for their roles in the DNA damage response and are the primary targets of FDA-approved inhibitors, the 'other' isoforms (PARP3 through PARP16) serve diverse and often specialized biological roles (Gupte et al., 2017). For example, PARP3 is involved in double-strand break repair and centrosome regulation, while PARP5a and PARP5b, also known as Tankyrases, regulate Wnt signaling and telomere length (Riffell et al., 2012). Many clinical PARP inhibitors exhibit varying degrees of cross-reactivity with these other isoforms; for instance, Olaparib and Rucaparib also inhibit PARP3, which may influence their overall clinical profile (Antolin & Mestres, 2014). Research into these additional family members is expanding, as selective inhibition of specific isoforms like the Tankyrases offers potential therapeutic avenues in cancers driven by Wnt signaling, such as colorectal cancer (Mashimo et al., 2019). However, the lack of high-resolution structural data and specific chemical probes for many of these mono-ADP-ribosyltransferases remains a challenge for drug development (Venkannagari et al., 2016). Understanding the distinct functions of these isoforms is critical for minimizing off-target toxicities, such as the hematological side effects often associated with non-selective PARP inhibition (Murai et al., 2012). Consequently, the development of isoform-selective inhibitors is a major focus in current medicinal chemistry to improve the therapeutic index of PARP-targeted therapies.

Other names

ARTD familyADP-ribosyltransferasesNon-PARP1/2 isoformsTankyrasesVault PARP

Inhibition of poly- or mono-ADP-ribosylation by competing with NAD+ for the catalytic binding site of the PARP enzyme.