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Design, Synthesis and Biological Evaluation of Novel MDH Inhibitors Targeting Tumor Microenvironment.


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.

SUBMITTER: Godesi S 

PROVIDER: S-EPMC10263210 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Design, Synthesis and Biological Evaluation of Novel MDH Inhibitors Targeting Tumor Microenvironment.

Godesi Sreenivasulu S   Han Jeong-Ran JR   Kim Jang-Keun JK   Kwak Dong-Ik DI   Lee Joohan J   Nada Hossam H   Kim Minkyoung M   Yang Hyun-A HA   Im Joo-Young JY   Ban Hyun Seung HS   Lee Chang Hoon CH   Choi Yongseok Y   Won Misun M   Lee Kyeong K  

Pharmaceuticals (Basel, Switzerland) 20230502 5


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 <b>50</b> containing a piperidine ring displayed an improved growth inhibition of A549 and H460 lung cancer cell lines compared with <b>LW1497</b>. Compound <b>50</b> reduced the total ATP content in A549 cells in a dose-dependent  ...[more]

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