Hartmut Beck

BAY 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I

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.

Inhibition of hypoxia-induced gene transcription by substituted pyrazolyl oxadiazoles: initial lead generation and structure-activity relationships.

The transcription factors hypoxia‐inducible factor‐1 and ‐2 (HIF‐1 and HIF‐2) orchestrate a multitude of processes that allow tumor cells to survive under conditions of low oxygen and nutrients, and that lead to resistance to some apoptotic pathways and facilitate invasion and metastasis. Therefore, inhibition of transactivation by HIF has become an attractive target in cancer research. Herein we present the results of a cell‐based screening approach that led to the discovery of substituted 1H‐pyrazole‐3‐carboxamides. Chemical optimization of the hit class with respect to potency and metabolic stability is described; it resulted in novel 5‐(1H‐pyrazol‐3‐yl)‐1,2,4‐oxadiazoles that inhibit the hypoxia‐induced accumulation of HIF‐1α and HIF‐2α. The HIF inhibitory potency in the screening cell system was improved from IC50 190 to 0.7 nM, and significant parts of the SAR are disclosed. For a key compound, the ability to suppress the hypoxia‐induced expression of HIF target genes was studied in A549 human lung adenocarcinoma cells. The same compound shows a favorable pharmacokinetic profile in rats after i.v. and p.o. administration.