Recent development in the discovery of PARP inhibitors as anticancer agents: a patent update (2016-2020).

INTRODUCTION: Discovery of small molecules that impede the activity of single-strand DNA repair enzyme, PARP1, has led to four marketed drugs for the treatment of advanced-stage cancers. Hence, there is a renewed enthusiasm in the PARP inhibitor discovery arena. To reduce nonspecific interactions or potential toxicities, and to understand the role of other minimally explored PARP enzymes, exciting new findings have emerged toward the development of selective inhibitors and targeted chemical biology probes. Importantly, the conventional PARP inhibitor design has evolved in a way that could potentially lead to multienzyme-targeting - a polypharmacological approach against aggressive cancers.

AREAS COVERED: This review comprises recent progress made in the development of PARP inhibitors, primarily focused on human cancers. Discovery of novel PARP inhibitors with pan, selective, and multi-target inhibition using in vitro and in vivo cancer models is summarized and critically evaluated. Emphasis is given to patents published during 2016-2020, excluding TNKS 1/2 inhibitors.

EXPERT OPINION: The outstanding success demonstrated by the FDA approved PARP inhibitors has fueled further clinical evaluations for expansion of their clinical utilities. The current clinical investigations include new candidates as well as marketed PARP-targeted drugs, both as single agents and in combination with other chemotherapeutics. Recent advances have also unveiled critical roles of other PARPs in oncogenic signal transduction, in addition to those of the well-documented PARP1/2 and TNKS1/2 enzymes. Further studies on lesser-known PARP members are urgently needed for functional annotations and for understanding their roles in cancer progression and other human diseases.