Abstract 758: Studies in cancer models with AGX51, a Direct Transcriptional RegulatorTM.
Authors: Garland William , Salvador Richard , Chaudhary Jaideep 
Published: August 2014

Abstract
Studies in cancer models with AGX51, a Direct Transcriptional RegulatorTM
The inhibitors of differentiation (Id) proteins (Id1, Id2, Id3, and Id4) are negative regulators of differentiation that act by sequestering basic helix loop helix (bHLH, e.g. E47) transcription factors. Ids are highly expressed during embryonic development but in adult tissues their expression is rare to absent. However, Id proteins are required for tumor angiogenesis, highly expressed in many cancers and as shown in many clinical studies, associated with an aggressive phenotype and a poor clinical outcome As a proof of concept, decreased angiogenesis and tumor load as a result of blocking Id expression by antisense and siRNA molecules demonstrated that Id is a compelling anti-cancer target. Despite these findings, the Ids are a heretofore unexplored target for the treatment of cancer. While no anti-Id agent has been studied clinically or has undergone preclinical development, AGX recently discovered and patented the first unique and potent anti-Id agent, AGX51. This small molecule is an inhibitor of the Id1-E47 interaction and was discovered through a systematic research effort using x-ray crystallography, gel shift (EMSA) assays, Matrigel evaluations and xenograft studies. AGX51 is the founding member of a new class of therapeutics: Direct Transcriptional RegulatorsTM.
In preclinical studies: (1) At a dose below 7 mg/kg, bid, AGX51 significantly blocked the growth of tumors in mice with implanted human breast cancer cells when treated briefly with a taxane like Taxol®, paclitaxel, or Taxotere®, docetaxel. This effect of AGX51 was expected based on the discovery that endothelial cell production in the bone marrow is responsible for the rapid repair to damaged vasculature after administration of paclitaxel or vascular disrupters such as ZD6126 or AVE8062, through mobilization of endothelial precursor cells (EPCs) followed by homing of the EPCs to the damaged vasculature; (2) At a dose below 20 nM, AGX51 restored cell cycle control in DU-145 human prostate cancer cells; (3) At low micromolar concentrations, AGX51 blocked migration of DU-145 cancer cells in “scratch” assays; (4) As a single agent, AGX51 completely blocked tumor associated angiogenesis in nude mice implanted with MDA-MB231 human breast cancer cells at a dose of 60 mg/kg, bid; (5) As expected, AGX51 restored levels of p21 and p27, two important mediators of cell cycle regulation in both PC3 and DU145 cancer cells; (6) AGX51 caused no toxicity in multiple day dosing based on weight, clinical chemistry or hematology measurements; (7) AGX51 has a terminal elimination half-life in mice of approximately 6 hours, which is suggestive of ultimate bid and perhaps even qd dosing in man. In summary, a specific inhibitor of Id-E47 interaction that has anti-tumor activity is described for the first time. This research was supported by AngioGenex, Inc.
Citation Format: William Garland, Richard Salvador, Jaideep Chaudhary. Studies in cancer models with AGX51, a Direct Transcriptional RegulatorTM. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 758. doi:10.1158/1538-7445.AM2013-758