Pharmaceuticals (May 2023)

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

  • Sreenivasulu Godesi,
  • Jeong-Ran Han,
  • Jang-Keun Kim,
  • Dong-Ik Kwak,
  • Joohan Lee,
  • Hossam Nada,
  • Minkyoung Kim,
  • Hyun-A Yang,
  • Joo-Young Im,
  • Hyun Seung Ban,
  • Chang Hoon Lee,
  • Yongseok Choi,
  • Misun Won,
  • Kyeong Lee

DOI
https://doi.org/10.3390/ph16050683
Journal volume & issue
Vol. 16, no. 5
p. 683

Abstract

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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.

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