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BAY 87-2243, a Highly Potent and Selective Inhibitor of Hypoxia-Induced Gene Activation Has Antitumor Activities by Inhibition of Mitochondrial Complex I

BAY 87-2243, a Highly Potent and Selective Inhibitor of Hypoxia-Induced Gene Activation Has Antitumor Activities by Inhibition of Mitochondrial Complex I

Peter Ellinghaus, Iring Heisler, Kerstin Unterschemmann, Michael Haerter, Hartmut Beck, Susanne Greschat, Alexander Ehrmann, Holger Summer, Ingo Flamme, Felix Oehme, Karlheinz Thierauch, Martin Michels, etc.

Cancer Med. 2013 Oct;2(5):611-24.

PMID: 24403227

Abstract:

The activation of the transcription factor hypoxia-inducible factor-1 (HIF-1) plays an essential role in tumor development, tumor progression, and resistance to chemo- and radiotherapy. In order to identify compounds targeting the HIF pathway, a small molecule library was screened using a luciferase-driven HIF-1 reporter cell line under hypoxia. The high-throughput screening led to the identification of a class of aminoalkyl-substituted compounds that inhibited hypoxia-induced HIF-1 target gene expression in human lung cancer cell lines at low nanomolar concentrations. Lead structure BAY 87-2243 was found to inhibit HIF-1α and HIF-2α protein accumulation under hypoxic conditions in non-small cell lung cancer (NSCLC) cell line H460 but had no effect on HIF-1α protein levels induced by the hypoxia mimetics desferrioxamine or cobalt chloride. BAY 87-2243 had no effect on HIF target gene expression levels in RCC4 cells lacking Von Hippel-Lindau (VHL) activity nor did the compound affect the activity of HIF prolyl hydroxylase-2. Antitumor activity of BAY 87-2243, suppression of HIF-1α protein levels, and reduction of HIF-1 target gene expression in vivo were demonstrated in a H460 xenograft model. BAY 87-2243 did not inhibit cell proliferation under standard conditions. However under glucose depletion, a condition favoring mitochondrial ATP generation as energy source, BAY 87-2243 inhibited cell proliferation in the nanomolar range. Further experiments revealed that BAY 87-2243 inhibits mitochondrial complex I activity but has no effect on complex III activity. Interference with mitochondrial function to reduce hypoxia-induced HIF-1 activity in tumors might be an interesting therapeutic approach to overcome chemo- and radiotherapy-resistance of hypoxic tumors.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1227158851	BAY 87-2243		1227158-85-1	Price

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