A Novel Malate Dehydrogenase 2 Inhibitor Suppresses Hypoxia-Inducible Factor-1 by Regulating Mitochondrial Respiration

Abstract

We previously reported that hypoxia-inducible factor (HIF)-1 inhibitor LW6, an aryloxyacetylamino benzoic acid derivative, inhibits malate dehydrogenase 2 (MDH2) activity during the mitochondrial tricarboxylic acid (TCA) cycle. In this study, we present a novel MDH2 inhibitor compound 7 containing benzohydrazide moiety, which was identified through structure-based virtual screening of chemical library. Similar to LW6, compound 7 inhibited MDH2 activity in a competitive fashion, thereby reducing NADH level. Consequently, compound 7 reduced oxygen consumption and ATP production during the mitochondrial respiration cycle, resulting in increased intracellular oxygen concentration. Therefore, compound 7 suppressed the accumulation of HIF-1α and expression of its target genes, vascular endothelial growth factor (VEGF) and glucose transporter 1 (GLUT1). Moreover, reduction in ATP content activated AMPK, thereby inactivating ACC and mTOR the downstream pathways. As expected, compound 7 exhibited significant growth inhibition of human colorectal cancer HCT116 cells. Compound 7 demonstrated substantial anti-tumor efficacy in an in vivo xenograft assay using HCT116 mouse model. Taken together, a novel MDH2 inhibitor, compound 7, suppressed HIF-1α accumulation via reduction of oxygen consumption and ATP production, integrating metabolism into anti-cancer efficacy in cancer cells.

Hypoxia‐inducible factor‐1 (HIF‐1) inhibitors from the last decade (2007 to 2016): A “structure–activity relationship” perspective

“…New HIF‐1 inhibitors have also been reported based on this new target MDH2. Calcineurin B homologous protein 1 (CHP1) was another molecular target protein identified as a target of LW6 in other studies . In another study, we found that heat shock protein (HSP) 70 was a target protein of the phase I clinical candidate adamantyl‐based derivative IDF‐11774 …”

“…Calcineurin B homologous protein 1 (CHP1) was another molecular target protein identified as a target of LW6 in other studies. [23][24][25][26] In another study, we found that heat shock protein (HSP) 70 was a target protein of the phase I clinical candidate adamantyl-based derivative IDF-11774. 27 LW6-based chemical probes were selected from a SAR study of various chemical probes synthesized in our lab.…”

Liver X Receptor Agonist Therapy Prevents Diffuse Alveolar Hemorrhage in Murine Lupus by Repolarizing Macrophages

“…The transcriptional program induced by HIF1α is important for Mϕ and neutrophil function in infected (hypoxic) tissues ( 32 ). HIF targets include genes involved in aerobic glycolysis as well as inflammation ( 17 , 33 ). The M1 marker CD274 (PD-L1) is HIF1α regulated and was expressed at higher levels in Mϕ from pristane- vs. MO-treated mice (Figure 3 A).…”

“…Our data suggested that HIF1α inhibitors or LXR agonists might benefit lupus patients by promoting M2 Mϕ polarization. Selective HIF1α inhibitors are not readily available, although there is interest in targeting the HIF1α activation pathway for cancer therapy ( 33 , 37 ). Synthetic LXR agonists protect mice from atherosclerosis, myocardial ischemia-perfusion injury, and other conditions ( 26 , 38 ).…”

The spatial metabolic heterogeneity of solid type of Ehrlich carcinoma

“…Активность НАДМДГ максимальна в центральной, а также в правой верхней областях исследованного фрагмента (ряд 1, столбец 4; ряд 2, столбец 3). На основании того, что НАДМДГ также является одним из ферментов, которые определяют интенсивность субстратного потока в ЦТК, при повышении его активности можно предположить возрастание уровня аэробных энергетических процессов в клетках опухоли [9]. Максимум активности НАДНМДГ наблюдается в смежной области исследованного фрагмента (ряд 2, столбец 4), правее и ниже максимума активности НАДМДГ.…”