Tankyrase inhibitors as antitumor agents: a patent update (2013 – 2020)

ABSTRACT

Introduction

Tankyrase inhibitors gained significant attention as therapeutic targets in oncology because of their potency. Their primary role in inhibiting the Wnt signaling pathway makes them an important class of compounds with the potential to be used as a combination therapy in future treatments of colorectal cancer.

Areas covered

This review describes pertinent work in the development of tankyrase inhibitors with a great emphasis on the recently patented TNKS inhibitors published from 2013 to 2020. This article also highlights a couple of promising candidates having tankyrase inhibitory effects and are currently undergoing clinical trials.

Expert opinion

Following the successful clinical applications of PARP inhibitors, tankyrase inhibition has gained significant attention in the research community as a target with high therapeutic potential. The ubiquitous role of tankyrase in cellular homeostasis and Wnt-dependent tumor proliferation brought difficulties for researchers to strike the right balance between potency and on-target toxicity. The need for novel tankyrase inhibitors with a better ADMET profile can introduce an additional regimen in treating various malignancies in monotherapy or adjuvant therapy. The development of combination therapies, including tankyrase inhibitors with or without PARP inhibitory properties, can potentially benefit the larger population of patients with unmet medical needs.

KEYWORDS:

• Cancer
• lactams
• PARP
• tankyrase
• TNKS inhibitors
• wnt/β-catenin signaling pathway

Abbreviations

TNKS: Tankyrases

TNKSi: Tankyrase inhibitors

PARP: Poly(ADP-ribose) polymerase

APC: Adenomatous polyposis coli

HTRF: Homogeneous time-resolved fluorescence

TR-FRET: Time released-fluorescence resonance energy transfer

STF: Super TopFlash (luciferase reporter gene assay)

Article highlights

• This review describes tankyrase inhibitors patented between 2013 and 2020 for enhanced potency and antitumor activity.

• All therapeutic patents are categorized based on the structural features of the reported TNKS inhibitors.

• The sensitivity and tumor responsiveness of TNKS inhibitors have been discussed as described in the reports.

• Candidates reached in clinical trials as tankyrase inhibitors from 2013 to 2020 are reviewed.

• The synthetic route for a recently developed clinical candidate has been described.

• Applications of TNKS inhibitors are aimed for the treatment of cancers; in most cases, colorectal cancer through inhibition of aberrant Wnt/β-catenin pathway.

• The scope of inclusion of TNKS inhibitors in combination therapy through increased sensitization and synergistic inhibition of oncogenic pathways has been discussed.

This box summarizes the key points contained in the article.

Acknowledgments

The authors are thankful to Nirma University, Ahmedabad, India for this work, which is a part of the Doctor of Philosophy (PhD) research work of Chirag C. Mehta, to be submitted to Nirma University, Ahmedabad, India.

Declaration of interest

The authors have no 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 of this manuscript has disclosed that they are an inventor in patent applications discussed in this review. All other peer reviewers in this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.