Open AccessEfficacy and mechanism of KRAS G12C PROTAC in inhibiting the proliferation of pancreatic cancer cells
Author(s) -
Shuai Gao,
AUTHOR_ID,
Fangxia Zou,
Lianfang Zheng,
Yunjie Wang,
Xinyu Feng,
Deshuai Liu,
Yutong Mao,
Y. T. Liang,
Jingwei Tian,
AUTHOR_ID,
AUTHOR_ID,
AUTHOR_ID,
AUTHOR_ID,
AUTHOR_ID,
AUTHOR_ID,
AUTHOR_ID,
AUTHOR_ID
Publication year - 2022
Publication title -
journal of pharmaceutical and biopharmaceutical research
Language(s) - English
Resource type - Journals
ISSN - 2630-533X
DOI - 10.25082/jpbr.2021.01.002
Subject(s) - kras , pancreatic cancer , cancer research , proteasome , apoptosis , cell cycle , cancer , cancer cell , cell growth , protein degradation , viability assay , medicine , biology , microbiology and biotechnology , colorectal cancer , biochemistry
Pancreatic cancer is a rare but highly malignant cancer with few effective treatments available. Targeting cancers bearing specific genetic mutations offers a new approach for cancer therapy. PROTAC (proteolysis-targeting chimeras) is an emerging technique to design targeted therapy and increasing evidence supports its utility. This study examined the in vitro pharmacodynamics and mechanism of PROTAC K-Ras Degrader-1 (PKD-1), a PROTAC molecule, in inhibiting the proliferation of pancreatic cancer cells. We used a pancreatic cancer cell line, MIA PaCa-2 cells, to examined the binding and degradation-promoting capabilities of PKD-1 on KRAS G12C protein and further evaluated the effects of PKD-1 on cell viability, cell cycle and apoptosis. PKD-1 was able to bind to KRAS G12C protein, promoted its degradation for up to 72 h, reduced cell viability, increased cell cycle arrest and promoted cell apoptosis. Mechanistic study found that the efficacy of PKD-1 was at least partially mediated by promoting 26S proteasome degradation process. Combined, these results extended previous findings and support the potential utility of PROTAC molecules such as PKD-1 as a new treatment strategy against pancreatic cancer.