Preclinical Evaluation Of Novel Hif-1 Alpha/P300 Binding Inhibitors

A key component of tumor progression and metastasis is the hypoxic response. The hypoxic response regulates angiogenesis, tumor invasion, and metabolism. The Hypoxia Inducible Factor (HIF) is the transcriptional system responsible for the hypoxic response. The inhibition of the hypoxic response via inhibition of the HIF-1 pathway by disrupting its association with the transcriptional coactivator p300 presents a potential therapeutic target for multiple cancers where HIF is upregulated. To that end, we describe the preclinical development of previously described novel marine pyrroloiminoquinone alkaloids found using a HIF-1α/p300 assay in a high throughput screen of extracts from the National Cancer Institute9s Natural Products Repository. Pyrroloiminoquinone alkaloids are a novel class of HIF-1α inhibitors, which interrupt the protein−protein interaction between HIF-1α and p300 and consequently reduce HIF-related transcription. The 2 lead candidates, discorhabdin L and H were assessed in inhibition of angiogenesis in an in vitro HUVEC assay and ex vivo rat aortic ring assay. The compounds were also evaluated for in vivo efficacy in prostate cancer cell tumor xenografts. Results show that development of these compounds for clinical use is warranted and may prevent the progression of multiple tumor types. Citation Format: Jonathan D. Strope, Emily M. Harris, Shaunna L. Beedie, Cindy H. Chau, Kristina M. Cook, Christopher J. Schofield, Kirk R. Gustafson, William D. Figg. Preclinical evaluation of novel HIF-1α/P300 binding inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 14.