Discovery of the First Lactate Dehydrogenase Proteolysis Targeting Chimera Degrader for the Treatment of Pancreatic Cancer

Lactate dehydrogenase (LDH) is a key glycolytic enzyme and biomarker of aggressive cancers. LDHA and LDHB are two main LDH subunits, and both are frequently overexpressed in tumors and essential for tumor growth. A number of LDHA/B small-molecule inhibitors have been developed. Here, we report the discovery of the first LDH proteolysis targeting chimera (PROTAC) degrader, compound 22 (MS6105). 22 potently degraded LDHA in a time-and ubiquitin-proteasome system dependent manner. Using an unbiased global proteomic study, we confirmed that 22 degraded both LDHA and LDHB significantly. 22 was significantly more potent than the parent LDH inhibitor in suppressing the growth of both quasi-mesenchymal state and epithelial state pancreatic cancer cell lines. Furthermore, 22 was bioavailable in mice through intraperitoneal injection. Overall, 22 could be a valuable chemical tool for the research community to explore pathophysiological functions of LDH in vitro and in vivo.

Automated summary

Lactate dehydrogenase (LDH) is a key glycolytic enzyme and biomarker of aggressive cancers. LDHA/B inhibitors have been developed, but here, researchers report the discovery of a LDH proteolysis targeting chimera (PROTAC) degrader, compound 22 (MS6105), which potently degrades LDHA and LDHB in a time- and ubiquitin-proteasome system dependent manner. Compound 22 shows stronger inhibitory effects on pancreatic cancer cell growth compared to the parent LDH inhibitor, and it is bioavailable in mice through intraperitoneal injection. Overall, compound 22 could be a valuable tool for studying the pathophysiological functions of LDH in vitro and in vivo.