TY - JOUR
T1 - Discovery of the First Lactate Dehydrogenase Proteolysis Targeting Chimera Degrader for the Treatment of Pancreatic Cancer
AU - Sun, Ning
AU - Kabir, Md
AU - Lee, Youngeun
AU - Xie, Ling
AU - Hu, Xiaoping
AU - Velez, Julia
AU - Chen, Xian
AU - Kaniskan, H. Ümit
AU - Jin, Jian
N1 - Funding Information:
J.J. acknowledges the support by an endowed professorship by the Icahn School of Medicine at Mount Sinai and grant P30CA196521 from the National Cancer Institute (NCI) at the National Institutes of Health (NIH). M.K. was supported by the Training Grant in Cancer Biology (T32CA078207) from the NCI. This work utilized the NMR Spectrometer Systems at Mount Sinai acquired with funding from the NIH’s SIG grants 1S10OD025132 and 1S10OD028504.
Publisher Copyright:
© 2023 American Chemical Society. All rights reserved.
PY - 2023/1/12
Y1 - 2023/1/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85144399598&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.2c01505
DO - 10.1021/acs.jmedchem.2c01505
M3 - Article
C2 - 36538511
AN - SCOPUS:85144399598
SN - 0022-2623
VL - 66
SP - 596
EP - 610
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 1
ER -