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

Introduction: RIP1 kinase is a serine/threonine-protein kinase that has recently emerged as a central regulator of TNF-alpha 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.