Development of Potent and Selective RIPK1 Degraders Targeting Its Nonenzymatic Function for Cancer Treatment

Receptor-interacting
protein kinase 1 (RIPK1) is a threonine/serine
kinase that serves as a critical regulator of immune responses and
cell death pathways, functioning through both its kinase activity
and nonenzymatic scaffolding function. The scaffolding function of
RIPK1 contributes to both intrinsic and extrinsic resistance to immune
checkpoint blockades (ICBs), making it a compelling therapeutic target
for cancer treatment. Recent studies have highlighted RIPK1’s
potential as a key modulator for improving the efficacy of immune-stimulatory
therapies, such as ICBs and X-ray radiotherapy (XRT). In this study,
we have developed a highly potent and selective RIPK1 degrader. When
combined with XRT, the degrader significantly suppressed tumor growth,
achieving enhanced therapeutic efficacy without apparent adverse effects.
In contrast, the RIPK1 inhibitor showed no notable therapeutic effect.
These findings underscore the potential of targeting RIPK1 degradation,
specifically its nonenzymatic function, as a novel strategy to augment
the effects of radiotherapy.