Inhibitors of RIP1 kinase: a patent review (2016–present)

ABSTRACT

Introduction: RIP1 kinase is a serine/threonine-protein kinase that has recently emerged as a central regulator of TNF-α dependent programmed necrosis (necroptosis), an inflammatory form of cell death, with important roles in inflammation and neurodegeneration. Small molecule RIP1 kinase inhibitors may provide new opportunities for treating a variety of autoimmune, inflammatory, and neurodegenerative diseases, among others, and thus have attracted widespread drug development efforts and a corresponding large amount of patent activity in recent years.

Areas covered: This review focuses on the patent literature covering small molecule inhibitors of RIP1 kinase from 2016–present.

Expert opinion: Inhibition of programmed necrosis (necroptosis) by RIP1 kinase inhibitors is a new field that has attracted widespread recent interest as a possible therapeutic means to treat a number of diseases in the inflammatory, neurodegenerative, and oncology areas. The interest in the therapeutic potential of RIP1kinase is evidenced by more than 40 small molecule patent applications published since 2016. To date, only a few RIP1 kinase inhibitors have entered the clinic. An understanding of the optimal clinical setting, in terms of dosing and disease indications for RIP1 inhibition, will require further clinical readouts as the current inhibitors progress and additional molecules enter into full development.

KEYWORDS:

• RIP1 kinase
• allosteric inhibitors
• necroptosis inhibition
• inflammation
• neurodegeneration

Article highlights

• A detailed review of the patent literature for RIP1 kinase inhibitors since 2016 is provided.

• The patents reviewed of RIP1 kinase inhibitors that bind in an allosteric pocket at the back of the ATP binding site include the necrostatin, benzoxazepinone, dihydropyrazole, pyrrolotriazole, pyrazolopyrazolone, and benzoxazepine series.

• A series of aminotriazolopyridines and benzothiazoles that are likely to be RIP1 kinase hinge binders (non-allosteric) are also reviewed.

• A summary of the initial clinical studies using RIP1 inhibitors GSK2982772 for psoriasis, rheumatoid arthritis, or intestinal bowel disease; DNL104 and DNL747 for Alzheimer’s or amyotrophic lateral sclerosis; GSK3145095 for pancreatic cancer and DNL758 for COVID-19 are described along with reported outcomes.

• This box summarizes key points contained in the article.

Declaration of interest

P Harris is a former employee of GlaxoSmithKline. The author has 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

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

Additional information

Funding

This paper was not funded.