A patent review of MAPK inhibitors (2018 – present)

ABSTRACT

Introduction

The mitogen-activated protein kinase (MAPK) family consist of p38 MAP kinases, c-Jun N-terminal kinases (JNKs) and extracellular signal-regulated kinases (ERKs). They are involved in a multitude of diseases, including inflammatory, autoimmune, neurodegenerative, and metabolic diseases as well as cancer. In recent years, further developments in the field of MAPK-inhibitors have been reported, including an isoform or downstream target selective inhibition of MAPKs as well as target protein degradation approaches.

Areas covered

This review summarizes newly patented MAPK-inhibitors that were claimed between 2018 and early 2023. Presented are the patents as well as their corresponding publications, the storyline of development, and clinical trials involving these compounds. This article elaborates a total of 27 patents, which were identified using established search engines.

Expert opinion

Although industrial research on MAPK-inhibitors has been ongoing for more than 20 years, novel clinical trials of MAPK-inhibitors as potential drug candidates are still being conducted in the period under review. Recently reported inhibitors show an excellent selectivity profile and are even achieving selectivity between closely related isoforms. This progression offers the possibility to eliminate unwanted side effects and may finally lead to the approval of the first MAPK-inhibitor.

KEYWORDS:

• C-Jun N-terminal kinase
• deuteration
• downstream target selectivity
• extracellular signal-regulated kinase
• isoform selectivity
• P38 MAP kinase
• mitogen-activated protein kinase
• protacs

Article highlights

• deuterated p38α and ERK1/2-inhibitors with improved pharmacokinetics

• downstream target selective p38α-inhibitors

• slightly isoform-selective p38δ-inhibitors

• Isoform-selective and blood-brain barrier penetrable JNK3-inhibitors

• Inhibitor series with some individual selectivity toward JNK1 and JNK2

• Novel PROTAC-based approaches for degradation of ERK5 and phosphorylated p38

Declaration of interests

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

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

Author contribution statement

VR. Wydra was responsible for researching, illustrating, and writing of chapter 3. RB. Ditzinger was responsible for researching, illustrating, and writing of the subchapters 2.1.–2.4. as well as for subchapter 4.1. NJ. Seidler was responsible for researching, illustrating, and writing of subchapter 2.5. FW. Hacker was responsible for researching, illustrating, and writing of the subchapters 4.2.–4.3. and, for generating Figure 1. Introduction, conclusion, and expert opinion were created in equal parts by all the authors mentioned above. S Laufer was the supervisor.

Additional information

Funding

This paper was not funded.