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- Title
Design, Synthesis and Biological Evaluation of Novel MDH Inhibitors Targeting Tumor Microenvironment.
- Authors
Godesi, Sreenivasulu; Han, Jeong-Ran; Kim, Jang-Keun; Kwak, Dong-Ik; Lee, Joohan; Nada, Hossam; Kim, Minkyoung; Yang, Hyun-A; Im, Joo-Young; Ban, Hyun Seung; Lee, Chang Hoon; Choi, Yongseok; Won, Misun; Lee, Kyeong
- Abstract
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.
- Subjects
BIOSYNTHESIS; PYRUVATE dehydrogenase kinase; TUMOR microenvironment; HYPOXIA-inducible factors; LUNG cancer
- Publication
Pharmaceuticals (14248247), 2023, Vol 16, Issue 5, p683
- ISSN
1424-8247
- Publication type
Article
- DOI
10.3390/ph16050683