Mixed Lineage Kinase Degrader

PROTAC MLKL Degrader-1 is a selective MLKL PROTAC degrader with a DC₅₀ of 2.4 μM. PROTAC MLKL Degrader-1 blocks necroptosis without modulating the phosphorylation of RIPK1 or RIPK3, and exhibits a linear correlation between MLKL levels and necroptotic cell death.

CEP1347-VHL-02 is a selective MLK3 PROTAC degrader that mediates MLK3 degradation via the ubiquitin-proteasome system, with a DC₅₀ of 50-300 nM. After degrading MLK3, CEP1347-VHL-02 inhibits downstream JNK signaling, induces G₂/M phase arrest and apoptosis in cancer cells, and suppresses their clonogenic, migratory and 3D sphere-forming abilities. CEP1347-VHL-02 can be used for the research of triple-negative breast cancer.

PROTAC MLKL Degrader-3 is a MLKL PROTAC degrader with DC₅₀ values of 248.9 nM (Hepa1-6) and 271.3 nM (HepG2), respectively. PROTAC MLKL Degrader-3 induces proteasome- and cereblon-dependent MLKL degradation via ubiquitination. PROTAC MLKL Degrader-3 reduces intratumoral MLKL levels and inhibits tumor growth in mice. PROTAC MLKL Degrader-3 can be used in the research of hepatocellular carcinoma.

PROTAC MLKL Degrader-2 is an orally active and highly selective mixed lineage kinase domain-like pseudokinase (MLKL) PROTAC degrader with a DC₅₀ of 0.012 μM. PROTAC MLKL Degrader-2 recruits the CRBN E3 ubiquitin ligase to form a ternary complex, leading to ubiquitination of MLKL and its degradation via a proteasome-dependent pathway. PROTAC MLKL Degrader-2 inhibits necroptosis, reduces ROS production, restores mitochondrial function, and ameliorates lysosomal dysfunction induced by necroptotic stimuli. PROTAC MLKL Degrader-2 degrades MLKL in xenograft mouse models. PROTAC MLKL Degrader-2 can be used in cancer-related research.