2. Academic Validation
  3. Discovery of the First Lactate Dehydrogenase Proteolysis Targeting Chimera Degrader for the Treatment of Pancreatic Cancer

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

  • J Med Chem. 2023 Jan 12;66(1):596-610. doi: 10.1021/acs.jmedchem.2c01505.
Ning Sun 1,  Md Kabir 1,  Youngeun Lee 1,  Ling Xie 2,  Xiaoping Hu 1,  Julia Velez 1,  Xian Chen 2,  H Ümit Kaniskan 1,  Jian Jin 1
Affiliations

Affiliations

  • 1 Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 2 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
PMID: 36538511 DOI: 10.1021/acs.jmedchem.2c01505
Abstract

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.

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