Abstract 617: Small molecule that simultaneously inhibits Myc oncoprotein and activates HIF1A

Abstract

Abstract Aberrant expression of Myc oncoproteins is a major causal factor in a large proportion of human cancer. In particular, MYCN oncogene amplification is one of the most powerful prognostic markers identified in the childhood cancer neuroblastoma and, as such, represents a valuable therapeutic target for the development of novel treatment approaches. A diverse chemical library of small molecules was screened using a cell-based assay to identify inhibitors of MYCN. Among a number of molecules identified as potential Myc inhibitors, M606 was found to reduce protein expression of MYCN and its downstream target genes in the MYCN-amplified neuroblastoma cell line BE(2)-C. A similar effect was also observed in a number of c-Myc over-expressing tumor cell lines. Analysis of signalling pathways affected by M606 using FACTORIAL™ technology (Attagene Inc.) indicated that this small molecule inhibited Myc mediated transcription in a dose-dependent manner. Interestingly, hypoxia inducible factor 1 alpha (HIF1A) was induced ∼100 fold. Consistently, we observed HIF1A protein accumulation and nuclear translocation post-M606 treatment under normoxic conditions accompanied by activation of transcription of the HIF1A target, VEGF. siRNA-mediated knockdown of c-Myc or HIF1A in HepG2 cells followed by M606 treatment demonstrated that downregulation of c-Myc and upregulation of HIF1A by M606 are two independent events. Furthermore, inhibition of HIF1A prolyl hydroxylases by dimethyloxalylglycine (DMOG) resulted in downregulation of c-Myc protein independent of any HIFA upregulation. These results suggest that the same molecular mechanism, targeted by M606 and presumably involving inhibition of prolyl hydroxylases, can affect both HIF1A and Myc but in opposite ways. Further development of this compound may be useful in the treatment of cancers in which Myc oncoproteins are overexpressed as well as in the treatment or prevention of ischemic injury since recent studies suggest HIF1A activation may protect against ischemia-reperfusion injury. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 617. doi:10.1158/1538-7445.AM2011-617