Novel Direct AMPK Activator Suppresses Non-Small Cell Lung Cancer through Inhibition of Lipid Metabolism

Non-small cell lung cancer (NSCLC) dominates almost 85% of all lung cancer cases, becoming top 1 killer in the whole world. The patients whom harbor epidermal growth factor receptor (EGFR) mutation become resistant to tyrosine kinase inhibitors (TKIs), such as gefitinib within 1 year treatment. Therefore, it is urgently needed to discover novel effective small molecule inhibitors for those patients. In recently years, lots of scientists claimed cancer cell on different metabolism way. They pointed out that interferance cancer cells metabolism could cut off energy supporting. This concept was become ture by Chair Prof. Liu Liang, Prof. Yao Xiao-Jun, Dr. Leung Lai-Han and their team from the State Key Laboratory of Quality Research in Chinese Medicine (Macau University of Science and Technology, MUST). They identified a new compound D561-0775 which can inhibit NSCLC TKIs resistance cell growth.

They anchored on a metabolism rate-limiting enzyme 5’-adenosine menophosphate-activated protein kinase (AMPK) as a promising anti-cancer target. Based on AMPK structure, they using molecular docking technique to screen the compound library which contains 12000 compounds. After cell vability and functional in vitro assay, they demonstrated that D561-0775 exhibited significant inhibitory effect on gefitinib-resistant NSCLC cell lines. Furthermore, D561-0775 showed a remarkable in vitro AMPK enzyme activation effect.

Taken together, D561-0775 displayed potential anti-cancer activity via inducing apoptosis, cell cycle arrest, suppressing glycolysis and cholesterol synthesis after activation of AMPK in gefitinib-resistant H1975 cells.

This founding discovered that D561-0775 has provided a new chemical structure. It poteinial could be developed as cancer drug for gefitinib-resistant NSCLC patients through regulating lipid metabolism by directly targeting at AMPK. This paper was publicated by the journal “ Oncotarget ” on October 12, 2017. The newly released Impact Factor for Oncotarget is 5.16 (Thomson Reuters, 2017).