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:10.3390/ph16050683

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

Department of Pharmacy

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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 language	English
Article number	683
Journal	Pharmaceuticals
Volume	16
Issue number	5
DOIs	https://doi.org/10.3390/ph16050683
State	Published - May 2023

Keywords

HIF-1α
MDH1/2
inhibitors
lung cancer

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "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.",

keywords = "HIF-1α, MDH1/2, inhibitors, lung cancer",

author = "Sreenivasulu Godesi and Han, {Jeong Ran} and Kim, {Jang Keun} and Kwak, {Dong Ik} and Joohan Lee and Hossam Nada and Minkyoung Kim and Yang, {Hyun A.} and Im, {Joo Young} and Ban, {Hyun Seung} and Lee, {Chang Hoon} and Yongseok Choi and Misun Won and Kyeong Lee",

note = "Publisher Copyright: {\textcopyright} 2023 by the authors.",

year = "2023",

month = may,

doi = "10.3390/ph16050683",

language = "English",

volume = "16",

journal = "Pharmaceuticals",

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T1 - Design, Synthesis and Biological Evaluation of Novel MDH Inhibitors Targeting Tumor Microenvironment

AU - Godesi, Sreenivasulu

AU - Han, Jeong Ran

AU - Kim, Jang Keun

AU - Kwak, Dong Ik

AU - Lee, Joohan

AU - Nada, Hossam

AU - Kim, Minkyoung

AU - Yang, Hyun A.

AU - Im, Joo Young

AU - Ban, Hyun Seung

AU - Lee, Chang Hoon

AU - Choi, Yongseok

AU - Won, Misun

AU - Lee, Kyeong

PY - 2023/5

Y1 - 2023/5

N2 - 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.

AB - 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.

KW - HIF-1α

KW - MDH1/2

KW - inhibitors

KW - lung cancer

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DO - 10.3390/ph16050683

M3 - Article

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SN - 1424-8247

VL - 16

JO - Pharmaceuticals

JF - Pharmaceuticals

IS - 5

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ER -

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

Abstract

Keywords

UN SDGs

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