Prudent tactics to sail the boat of PARP inhibitors as therapeutics for diverse malignancies

ABSTRACT

Introduction

PARP inhibitors block the DNA-repairing mechanism of PARP and represent a promising class of anti-cancer therapy. The last decade has witnessed FDA approvals of several PARP inhibitors, with some undergoing advanced-stage clinical investigation. Medicinal chemists have invested much effort to expand the structure pool of PARP inhibitors. Issues associated with the use of PARP inhibitors that make their standing disconcerting in the pharmaceutical sector have been addressed via the design of new structural assemblages.

Area covered

In this review, the authors present a detailed account of the medicinal chemistry campaigns conducted in the recent past for the construction of PARP1/PARP2 inhibitors, PARP1 biased inhibitors, and PARP targeting bifunctional inhibitors as well as PARP targeting degraders (PROTACs). Limitations associated with FDA-approved PARP inhibitors and strategies to outwit the limitations are also discussed.

Expert opinion

The PARP inhibitory field has been rejuvenated with numerous tractable entries in the last decade. With numerous magic bullets in hand coupled with unfolded tactics to outwit the notoriety of cancer cells developing resistance toward PARP inhibitors, the dominance of PARP inhibitors as a sagacious option of targeted therapy is highly likely to be witnessed soon.

KEYWORDS:

• PARP inhibitors
• BRCA mutations
• multitargeting agents
• PROTACs
• cancer
• DNA damage repair

Article highlights

• The last decade has witnessed FDA approvals of several PARP inhibitors and the emergence of some investigational PARP inhibitors.

• Despite demonstrating significant promise, PARP inhibitors are marred by several limitations, viz. narrow activity spectrum, acquired resistance, PARP1 trapping, and promiscuous PARP inhibitory profile.

• Issues associated with PARP inhibitors have been answered through new structural template assemblages.

• The design of PARP targeting bifunctional inhibitors can expand the activity spectrum of PARP inhibitors.

• With numerous magic bullets in hand, exhaustive explorations are required to be conducted at the clinical level to ascertain their conclusive benefits as cancer therapeutics.

Declaration of interest

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

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

K Nepali is supported by grants from the National Science and Technology Council of Taiwan (grant no. MOST 111-2320-B-038 -047 and NSTC-112-2320-B-038 -030).