A patent review of MALT1 inhibitors (2013-present)

ABSTRACT

Introduction

MALT1 is the only human paracaspase, a protease with unique cleavage activity and substrate specificity. As a key regulator of immune responses, MALT1 has attracted attention as an immune modulatory target for the treatment of autoimmune/inflammatory diseases. Further, chronic MALT1 protease activation drives survival of lymphomas, suggesting that MALT1 is a suitable drug target for lymphoid malignancies. Recent studies have indicated that MALT1 inhibition impairs immune suppressive function of regulatory T cells in the tumor microenvironment, suggesting that MALT1 inhibitors may boost anti-tumor immunity in the treatment of solid cancers.

Areas covered

This review summarizes the literature on MALT1 patents and applications. We discuss the potential therapeutic uses for MALT1 inhibitors based on patents and scientific literature.

Expert opinion

There has been a steep increase in MALT1 inhibitor patents. Compounds with high selectivity and good bioavailability have been developed. An allosteric binding pocket is the preferred site for potent and selective MALT1 targeting. MALT1 inhibitors have moved to early clinical trials, but toxicological studies indicate that long-term MALT1 inhibition can disrupt immune homeostasis and lead to autoimmunity. Even though this poses risks, preventing immune suppression may favor the use of MALT1 inhibitors in cancer immunotherapies.

KEYWORDS:

• MALT1
• allosteric inhibition
• autoimmunity
• cancer immunotherapy
• lymphoma
• proteases
• regulatory T cells

Article highlights

• -An overview of the pathophysiological functions of MALT1 protease is provided.

• -Different classes of MALT1 inhibitor compounds are summarized.

• -The mode of action of active and allosteric site MALT1 inhibitors is presented.

• -MALT1 protease inhibitor treatment for the treatment of malignant lymphoma is described.

• -The emerging option for using MALT1 inhibitors in anti-cancer immunotherapy is discussed.

Declaration of interest

Authors are employees of Helmholtz Zentrum München. D Krappmann is an inventor of MALT1 inhibitor patents and a member of the scientific advisory board of Monopteros Therapeutics. 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 the inventor/author of a patent/publication listed in this review article. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Notes

1. The activity data for compounds in WO2015/181747 are given in µM instead of nM. This has been corrected in the following patent application, as well as in the Novartis publications.

Additional information

Funding

This paper has been funded by the Deutsche Forschungsgemeinschaft SFB 1054 project A04 to DK.