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- W1983503886 abstract "Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DCThe HIF signaling pathway is a crucial way in which tumors can circumvent the constraints of regions of low oxygen (hypoxia) to induce angiogenesis and maintain proliferation. The oxygen regulated subunit of the transcription factor hypoxia-inducible factor 1 (HIF1), HIF1αlpha, is a positive factor in tumor growth and its expression has been correlated with poor patient prognosis in a number of settings.We here present in vitro and in vivo data for a novel series of orally available small-molecule HIF signaling modulators that show nanomolar inhibition of the HIF signaling pathway in addition to potent anti-proliferative activity against a large number of cell lines derived from solid and blood tumors (EC50 in the range 1-100nM). Phenotypically, the compounds elicit an initial G2/M arrest, followed by the induction of caspase-3/7 and the onset of apoptosis.The in vitro results also translate into in vivo animal models. The lead compounds from the series show efficacy in tumor xenograft mouse models, with dose-dependent tumor growth inhibition of 60-70% after oral dosing (MDA-MB-231 xenograft). Structural optimisation has additionally allowed us to improve the PK and physicochemical characteristics of the compounds, with a lead candidate currently in formal pre-clinical development with the aim of entering a Phase 1 clinical trial in multiple myeloma at the end of 2010.In conclusion, we believe that the development towards clinical Proof-of-Concept of this new class of dual-mechanism inhibitors of HIF signaling and cell proliferation presents a promising new option for cancer therapeutics.Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-294." @default.
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- W1983503886 date "2010-04-15" @default.
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- W1983503886 title "Abstract LB-294: Development and characterization of novel orally available hypoxia-inducible factor (HIF) signaling inhibitors as dual-mechanism cancer therapeutics" @default.
- W1983503886 doi "https://doi.org/10.1158/1538-7445.am10-lb-294" @default.
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