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

ABSTRACT

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.

KEYWORDS:

• PARP enzyme
• DNA repair
• cancer
• selective PARP inhibitors
• synthetic lethality
• PARP Patent
• polypharmacology

Article highlights

• This review discusses the recent development of PARP inhibitors with a major emphasis on patents related to anticancer drug discovery.

• Novel PARP inhibitory scaffolds along with optimization of previously reported scaffolds in patents from the year 2016-2020 are documented, along with the assessment of their in vitro and in vivo efficacy, as applicable.

• Patented chemical compounds designed to target a member of the PARP family selectively, along with their clinical relevance, are elaborated.

• Non-selective compounds designed to exhibit multi-target inhibition are also included.

• Finally, patents reporting the SAR of newer clinical candidates, including pamiparib and RBN-2397, are reviewed.

This box summarizes key points contained in the article.

Declaration of interest

TT Talele is a co-founder of Hysplex, LLC, with interests in PARP-inhibitor development. 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they are an inventor of a patent application on PARP10 inhibitor OUL35 and a partner of Fangorn biopharma company that is not anymore pursuing PARP inhibitor development. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.