Open Access Peer-reviewed Research Article

Main Article Content

Shuai Gao
Fangxia Zou
Lixia Zheng
Yunjie Wang
Xinyu Feng
Deshuai Liu
Yutong Mao
Liang Ye corresponding author
Jingwei Tian

Abstract

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.

Keywords
KRAS, KRAS G12C, PROTAC K-Ras Degrader-1, pancreatic cancer, apoptosis

Article Details

Supporting Agencies
This work was supported by the “Taishan Industry Leading Talent Laureate” and the “Major New Drugs Research & Development” special projects of Ministry of Science and Technology of PR China (No. 2018ZX09303015).
How to Cite
Gao, S., Zou, F., Zheng, L., Wang, Y., Feng, X., Liu, D., Mao, Y., Ye, L., & Tian, J. (2022). Efficacy and mechanism of KRAS G12C PROTAC in inhibiting the proliferation of pancreatic cancer cells. Journal of Pharmaceutical and Biopharmaceutical Research, 3(1), 176-184. https://doi.org/10.25082/JPBR.2021.01.002

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