Abstract 289: Hydrogen bond surrogate (HBS) helices as orthosteric regulator of hypoxia inducible transcription

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Hypoxia-Inducible Factor (HIF-1) is a heterodimeric transcriptional activator which plays a critical role in tumorigenesis and therefore is an important therapeutic target. Transcriptional activation of HIF-1 is known to involve the interaction between cysteine-histidine rich region1 (CH1) of a coactivator protein p300 or Creb Binding Protein (CBP) and C-terminal activation domain (C-TAD) of its α-subunit (HIF-1α C-TAD). Based on the hydrogen bond surrogate (HBS) approach, we have rationally designed stabilized alpha helix that can disrupt the binding interface between C-TAD domain of HIF-1α and CH1 domain of p300/CBP. We have shown by fluorescence polarization that such stabilized alpha helix mimetics can directly bind to the CH1 domain of p300 and also can disrupt the HIF-1α/p300 complex. HBS helix mimetics are also shown to selectively downregulate the hypoxia inducible genes in cell culture. Thus, orthosteric inhibition of the HIF-1 transcriptional complex by rationally designed helix mimetics offers a novel approach to downregulate the expression of key hypoxia inducible genes responsible for tumor progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 289. doi:1538-7445.AM2012-289