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

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Article number683
JournalPharmaceuticals
Volume16
Issue number5
DOIs
Publication statusPublished - 2023 May

Bibliographical note

Funding 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).

Publisher Copyright:
© 2023 by the authors.

Keywords

  • HIF-1α
  • inhibitors
  • lung cancer
  • MDH1/2

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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