934593-90-5Relevant articles and documents
NOVEL COMPOUND HAVING MALATE DEHYDROGENASE INHIBITORY ACTIVITY AND PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING CANCER COMPRISING SAME AS ACTIVE INGREDIENT
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Paragraph 0246; 0250; 0291; 0292, (2020/02/14)
The present invention relates to a compound exhibiting inhibitory activity of at least one of malate dehydrogenases I (MDH1) and malate dehydrogenases 2 (MDH2), and a pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient. The inventors of the present invention have experimentally confirmed that the compound exhibiting the MDH1 and/or MDH2 inhibitory activity has an inhibitory effect on mitochondrial respiration in cancer cells, an excellent inhibitory effect on cancer cell growth, etc. Thus, the compound of the present invention is expected to be effectively used as a pharmaceutical composition for treating cancer.
Methyl 3-(3-(4-(2,4,4-Trimethylpentan-2-yl)phenoxy)-propanamido)benzoate as a Novel and Dual Malate Dehydrogenase (MDH) 1/2 Inhibitor Targeting Cancer Metabolism
Naik, Ravi,Ban, Hyun Seung,Jang, Kyusic,Kim, Inhyub,Xu, Xuezhen,Harmalkar, Dipesh,Shin, Seong-Ah,Kim, Minkyoung,Kim, Bo-Kyung,Park, Jaehyung,Ku, Bonsu,Oh, Sujin,Won, Misun,Lee, Kyeong
, p. 8631 - 8646 (2017/11/03)
Previously, we reported a hypoxia-inducible factor (HIF)-1 inhibitor LW6 containing an (aryloxyacetylamino)benzoic acid moiety inhibits malate dehydrogenase 2 (MDH2) using a chemical biology approach. Structure-activity relationship studies on a series of (aryloxyacetylamino)benzoic acids identified selective MDH1, MDH2, and dual inhibitors, which were used to study the relationship between MDH enzyme activity and HIF-1 inhibition. We hypothesized that dual inhibition of MDH1 and MDH2 might be a powerful approach to target cancer metabolism and selected methyl-3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)-benzoate (16c) as the most potent dual inhibitor. Kinetic studies revealed that compound 16c competitively inhibited MDH1 and MDH2. Compound 16c inhibited mitochondrial respiration and hypoxia-induced HIF-1α accumulation. In xenograft assays using HCT116 cells, compound 16c demonstrated significant in vivo antitumor efficacy. This finding provides concrete evidence that inhibition of both MDH1 and MDH2 may provide a valuable platform for developing novel therapeutics that target cancer metabolism and tumor growth.
Synthesis and structure-activity relationship study of chemical probes as hypoxia induced factor-1α/malate dehydrogenase 2 inhibitors
Naik, Ravi,Won, Misun,Ban, Hyun Seung,Bhattarai, Deepak,Xu, Xuezhen,Eo, Yumi,Hong, Ye Seul,Singh, Sarbjit,Choi, Yongseok,Ahn, Hee-Chul,Lee, Kyeong
, p. 9522 - 9538 (2015/01/09)
A structure-activity relationship study of hypoxia inducible factor-1α inhibitor 3-aminobenzoic acid-based chemical probes, which were previously identified to bind to mitochondrial malate dehydrogenase 2, was performed to provide a better understanding of the pharmacological effects of LW6 and its relation to hypoxia inducible factor-1α (HIF-1α) and malate dehydrogenase 2 (MDH2). A variety of multifunctional probes including the benzophenone or the trifluoromethyl diazirine for photoaffinity labeling and click reaction were prepared and evaluated for their biological activity using a cell-based HRE-luciferase assay as well as a MDH2 assay in human colorectal cancer HCT116 cells. Among them, the diazirine probe 4a showed strong inhibitory activity against both HIF-1α and MDH2. Significantly, the inhibitory effect of the probes on HIF-1α activity was consistent with that of the MDH2 enzyme assay, which was further confirmed by the effect on in vitro binding activity to recombinant human MDH2, oxygen consumption, ATP production, and AMP activated protein kinase (AMPK) activation. Competitive binding modes of LW6 and probe 4a to MDH2 were also demonstrated.
Synthesis and biological evaluation of ortho-carborane containing benzoxazole as an inhibitor of hypoxia inducible factor (HIF)-1 transcriptional activity
Nakamura, Hiroyuki,Yasui, Yuka,Ban, Hyun Seung
, p. 189 - 194 (2013/11/19)
ortho-Carborane and adamantane containing benzoxazoles were synthesized by intramolecular dehydration of the corresponding phenoxyacetanilides. Among the compounds synthesized, ortho-carborane containing benzoxazole 2b which has a carboxylic group on the benzoxazole ring, exhibited significant inhibition of hypoxia-induced HIF-1 transcriptional activity with the IC50 value of 14.4 μM toward HeLa cell-based reporter gene assay.
ARYLOXY PHENOXY ACRYLIC COMPOUND HAVING HIF-1 INHIBITION ACTIVITY, METHOD FOR PREPARING SAME, AND PHARMACEUTICAL COMPOSITION CONTAINING SAME AS AN ACTIVE INGREDIENT
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Paragraph 0216; 0217; 0218, (2013/09/26)
The present invention relates to a compound inhibiting HF-1 activity, a preparation method of the same, and a pharmaceutical composition comprising the same as an active ingredient. The compound of the present invention demonstrates anticancer activity no
Identification of malate dehydrogenase 2 as a target protein of the HIF-1 inhibitor LW6 using chemical probes
Lee, Kyeong,Ban, Hyun Seung,Naik, Ravi,Hong, Ye Seul,Son, Seohyun,Kim, Bo-Kyung,Xia, Yan,Song, Kyung Bin,Lee, Hong-Sub,Won, Misun
supporting information, p. 10286 - 10289 (2013/10/21)
Tracking the target: To identify a protein that binds directly to the HIF-1α inhibitor LW6, a series of new chemical probes were synthesized with a clickable tag and/or a photoactivatable moiety. LW6 was found to be localized to the mitochondria (see picture) and MDH2 was identified as a target protein of LW6. These results indicate that the HIF-1α inhibitory activity of LW6 is a consequence of MDH2 suppression. Copyright
ARYLOXYPHENOXYACETYL-BASED COMPOUND HAVING HIF-1 INHIBITION ACTIVITY, PREPARATION METHOD THEREOF AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME AS AN ACTIVE INGREDIENT
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Page/Page column 14-15, (2012/05/05)
Disclosed are a compound inhibitory of HIF-1 activity, a method for preparing the same, and a pharmaceutical composition comprising the same as an active ingredient. The compound has anticancer activity which is attributable to its inhibitory activity against HIF-1, but not to non-selective cellular toxicity. Thus, having inhibitory activity against HIF-1, the compound or a pharmaceutically acceptable salt thereof can be used as an ingredient in an anticancer agent for various cancers including large intestine cancer, hepatic cancer, stomach cancer and breast cancer. Further, the compound or a pharmaceutically acceptable salt thereof is applicable to the treatment of diabetic retinopathy or arthritis which is aggravated upon the activation of VEGFA by HIF-1.
COMPOUNDS THAT INHIBIT HIF-1 ACTIVITY, THE METHOD FOR PREPARATION THEREOF AND THE PHARMACEUTICAL COMPOSITION CONTAINING THEM AS AN EFFECTIVE COMPONENT
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Page/Page column 26, (2009/12/24)
Disclosed herein are an HIF-1 inhibitor, a method for the preparation thereof, and a pharmaceutical composition comprising the same as an active ingredient. The HIF-1 inhibitor shows anticancer activity thanks to the inhibition activity against HIF-1, a transcription factor which plays an important role in the growth and metastasis of cancer, but not to general cytotoxicity. Thus, the HIF-inhibitor and a pharmaceutically acceptable salt thereof can be used as a therapeutic for various cancers such as liver cancer; stomach cancer and breast cancer. Also, the compound having inhibition activity against HIF-1 is useful in the treatment of diabetic retinopathy and arthritis, which are aggravated by HIF-1-mediated VEGF expression.
COMPOUNDS TEAT INHIBIT HBF-I ACTIVITY, THE METHOD FOR PREPARATION THEREOF AND THE PHARMACEUTICAL COMPOSITION CONTAINING THEM AS AN EFFECTIVE COMPONENT
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Page/Page column 30, (2008/06/13)
Disclosed herein are an HIF-I inhibitor, a method for the preparation thereof, and a pharmaceutical composition comprising the same as an active ingredient The BDDF-I inhibitor shows anticancer activity thanks to the inhibition activity against HIF-I, a transcription factor which plays an important role in the growth and metastasis of cancer, but not to general cytotoxicity. Thus, the HIF-inhibitor and a pharmaceutically acceptable salt thereof can be used as a therapeutic for various cancers such as liver cancer, stomach cancer and breast cancer. Also, the compound having inhibition activity against HDDF-I is useful in the treatment of diabetic retinopathy and arthritis, which are aggravated by HEF-l-mediated VEGF expression.
(Aryloxyacetylamino)benzoic acid analogues: A new class of hypoxia-inducible factor-1 inhibitors
Lee, Kyeong,Lee, Jeong Hyung,Boovanahalli, Shanthaveerappa K.,Jin, Yinglan,Lee, Mijeoung,Jin, Xuejun,Kim, Jin Hwan,Hong, Young-Soo,Lee, Jung Joon
, p. 1675 - 1684 (2008/02/01)
Structural modification of a compound discovered during screening using an HRE-dependent reporter assay has revealed a novel class of HIF-1 inhibitors, which potently inhibit the HIF-1α protein accumulation and its target gene expression under hypoxic conditions in human hepatocellular carcinoma Hep3B cells.
