Small-Molecule Inhibitors of Necroptosis: Current Status and Perspectives

Necroptosis, an important form of programmed cell death
(PCD),
is a highly regulated caspase-independent type of cell death that
plays a critical role in the pathophysiology of various inflammatory,
infectious, and degenerative diseases. Currently, receptor-interacting
protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like
protein (MLKL) have been widely recognized as critical therapeutic
targets of the necroptotic machinery. Targeting RIPK1, RIPK3, and/or
MLKL is a promising strategy for necroptosis-related diseases. Following
the identification of the first RIPK1 inhibitor Nec-1 in 2005, the
antinecroptosis field is attracting increasing research interest from
multiple disciplines, including the biological and medicinal chemistry
communities. Herein, we will review the functions of necroptosis in
human diseases, as well as the related targets and representative
small-molecule inhibitors, mainly focusing on research articles published
during the past 10 years. Outlooks and perspectives on the associated
challenges are also discussed.