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
In: Journal of Medicinal Chemistry, Jg. 60 (2017-10-16), S. 8631-8646
Online
unknown
Zugriff:
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.
Titel: |
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
|
---|---|
Autor/in / Beteiligte Person: | Hyun Seung Ban ; Kim, Inhyub ; Jang, Kyusic ; Harmalkar, Dipesh S. ; Ku, Bonsu ; Xu, Xuezhen ; Kim, Bokyung ; Park, Jaehyung ; Kim, Minkyoung ; Shin, Seong-Ah ; Oh, Sujin ; Naik, Ravi ; Won, Misun ; Lee, Kyeong |
Link: | |
Zeitschrift: | Journal of Medicinal Chemistry, Jg. 60 (2017-10-16), S. 8631-8646 |
Veröffentlichung: | American Chemical Society (ACS), 2017 |
Medientyp: | unknown |
ISSN: | 1520-4804 (print) ; 0022-2623 (print) |
DOI: | 10.1021/acs.jmedchem.7b01231 |
Schlagwort: |
|
Sonstiges: |
|