Recent developments and strategies for the discovery of TACE inhibitors

ABSTRACT

Introduction

TNF-α plays a central role in certain autoimmune diseases as well as in inflammation. The current strategy for excluding TNF-α from circulation is to selectively inhibit TNF-α converting enzyme (TACE), an enzyme that cleaves mTNF-α to active TNF-α. Various TACE inhibitors have been discovered by using different strategies to control inflammatory diseases, cancer, and cardiac hypertrophy.

Areas covered

The present article summarizes the design and discovery of novel TACE inhibitors that have been reported in the literature since 2012 onwards. It also includes some reports concerning the new role that TACE plays in cancer and cardiac hypertrophy.

Expert opinion

So far, undertaken studies that have looked to design and develop small TACE inhibitors have been discouraging due to the failure of any TACE inhibitors to hit the market. However, some of the latest developments, such as with tartrate-based inhibitors, has given hope to the potentiality of a viable novel selective TACE inhibitor therapeutic in the future. Indeed, some of the novel peptidomimetics and monoclonal antibodies have great potential to pave the way for an effective and safe therapy by selectively inhibiting TACE enzyme.

KEYWORDS:

• TNF-α
• TACE inhibitors
• design strategies
• rheumatoid arthritis

Article highlights

• TACE is a potential therapeutic target for treatment of rheumatoid arthritis, cancer, and cardiac hypertrophy.

• Selectivity is a major hurdle in targeting TACE.

• Zinc Binding Groups (ZBGs) play an important role in determining the efficacy, selectivity and toxicity of TACE inhibitors.

• Lack of selectivity and systemic toxicity are setbacks for hydroxamates.

• Some TACE inhibitors have been developed as topical treatments for dermatological conditions such as psoriasis and acne which limits their systemic toxicity.

• Research is underway to engineer monoclonal antibodies that are TACE inhibitors.

This box summarizes key points contained in the article.

Declaration of interest

MR Yadav is thankful to the University Grant Commission (UGC), New Delhi, for providing them with the UGC-BSR Faculty Fellowship [No. F.18-1/2011 (BSR)]. M Chauhan meanwhile gratefully acknowledges the ICMR, New Delhi for awarding them with the Senior Research Fellowship (F. No. Fellowship/TB/34/2019/ECD-I). 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

This manuscript has not been funded.