Discovery of a novel NUAK1 inhibitor against pancreatic cancer

Biomedicine & Pharmacotherapy

So Ha Lee¹  Jae Ho Kim¹  Kyung Hee Jung¹  Ji Eun Lee¹  Beom Seok Han²  Soyeon Ko³  Soon-Sun Hong³  Myeong-Seong Seo³  Sungwoo Hong³  Kewon Kim³ 

[1] Engineering, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 22332, South Korea;Center for Catalytic Hydrocarbon Functionalization, Institute of Basic Science (IBS) and Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea;;Department of Medicine, College of Medicine, and Program in Biomedical Science &

关键词: Apoptosis;    NUAK1;    KI-301670;    Pancreatic cancer;    PI3K/AKT pathway;   

DOI  :  

来源: DOAJ

【 摘 要 】

The novel (nua) kinase family 1 (NUAK1) is an AMPK-related kinase and its expression is associated with tumor malignancy and poor prognosis in several types of cancer, suggesting its potential as a target for cancer therapy. Therefore, the development of NUAK1-targeting inhibitors could improve therapeutic outcomes in cancer. We synthesized KI-301670, a novel NUAK1 inhibitor, and assessed its anticancer effects and mechanism of action in pancreatic cancer. It effectively inhibited pancreatic cancer growth and proliferation, and induced cell cycle arrest, markedly G0/G1 arrest, by increasing the expression of p27 and decreasing expression of p-Rb and E2F1. Additionally, the apoptotic effect of KI-301670 was observed by an increase in cleaved PARP, TUNEL-positive cells, and annexin V cell population, as well as the release of cytochrome c via the loss of mitochondrial membrane potential. KI-301670 inhibited the migration and invasion of pancreatic cancer cells. Mechanistically, KI-301670 effectively inhibited the PI3K/AKT pathway in pancreatic cancer cells. Furthermore, it significantly attenuated tumor growth in a mouse xenograft tumor model. Our results demonstrate that a novel NUAK1 inhibitor, KI-301670, exerts anti-tumor effects by directly suppressing cancer cell growth by affecting the PI3K/AKT pathway, suggesting that it could be a novel therapeutic candidate for pancreatic cancer treatment.

【 授权许可】

Unknown