MDH1 and MDH2 enzymes play an important role in the survival of lung cancer. In this study, a novel series of dual MDH1/2 inhibitors for lung cancer was rationally designed and synthesized, and their SAR was carefully investigated. Among the tested compounds, compound 50 containing a piperidine ring displayed an improved growth inhibition of A549 and H460 lung cancer cell lines compared with LW1497. Compound 50 reduced the total ATP content in A549 cells in a dose-dependent manner; it also significantly suppressed the accumulation of hypoxia-inducible factor 1-alpha (HIF-1α) and the expression of HIF-1α target genes such as GLUT1 and pyruvate dehydrogenase kinase 1 (PDK1) in a dose-dependent manner. Furthermore, compound 50 inhibited HIF-1α-regulated CD73 expression under hypoxia in A549 lung cancer cells. Collectively, these results indicate that compound 50 may pave the way for the development of next-generation dual MDH1/2 inhibitors to target lung cancer.
Bibliographical noteFunding Information:
This study was supported by a National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIT) [No. 2018R1A5A2023127, No. 2019M3E505066636, No. 2021R1A2C1013746, and No. 2023R1A2C3004599]. This work was also supported by the BK21 FOUR program and KRIBB Research Initiative Program (KGM5192322).
© 2023 by the authors.
- lung cancer
ASJC Scopus subject areas
- Molecular Medicine
- Pharmaceutical Science
- Drug Discovery