Discovery of Novel MLKL PROTAC Degraders for the Treatment of Hepatocellular Carcinoma via Promoting Parthanatos

Hepatocellular carcinoma (HCC) remains a leading cause
of cancer-related
mortality worldwide, primarily due to its low immunogenicity and immunosuppressive
tumor microenvironment. Inducing immunogenic cell death (ICD), a regulated
form of cell death with the capacity to enhance tumor immunogenicity
and activate antitumor immune responses, has emerged as a pivotal
anticancer strategy. Mixed lineage kinase domain-like pseudokinase
(MLKL) is a terminal-known obligate effector in the process of necroptosis,
a programmed cell death pathway. Although several ATP competitive
inhibitors of MLKL were reported, these inhibitors were unable to
prevent the function of MLKL, rendering MLKL seemingly “undruggable.”
Moreover, the majority of research on MLKL focused on its biological
role in necroptosis, and the investigation of its non-necroptotic
functions has rarely been reported. Here, we report the discovery
of C116 as a potent and selective MLKL degrader through
leveraging artificial intelligence-assisted ligand discovery combined
with targeted protein degradation technology. Notably, C116 effectively induces MLKL degradation and promotes parthanatos in
HCC cells. More importantly, C116 was able to induce
in vivo MLKL degradation and exerts strong antitumor activities in
an orthotopic HCC tumor model, positioning it as a promising starting
point for the treatment of HCC and for investigating the non-necroptotic
functions of MLKL.