Abstract LB-385: Pre-clinical development of the novel, broad spectrum, anti-cancer agent EL102
Authors: McLaughlin Fiona , McLaughlin Fiona 
Published: August 2014

Abstract
Introduction
EL102 was identified using a systems biology approach to develop novel small molecule antagonists of the hypoxia signalling cascade. EL102 inhibits HIF1alpha signalling in cells with and IC50 of approximately 13 nM. In addition to the potent inhibition of HIF1alpha signalling, EL102 causes a reduction in cellular proliferation across a broad range of solid and liquid tumor cells with IC50 values in the low nM range. At these concentrations, EL102 induces caspase 3/7 and drives cells into apoptosis. Further characterisation of EL102 was undertaken in human xenografts as a single agent, where significant tumor growth reduction (TGI 69%) was observed at concentrations that did not produce significant body weight loss. Due to its favourable pharmacokinetic and physiochemical properties, EL102 was subsequently selected as a clinical development candidate and entered formal pre-clinical development studies in late 2010. The anticipated date of Phase I entry is 2H 2011.
Objectives
The objectives of this study were to define the mechanism of action of the clinical development candidate EL102 and to identify the best dose and schedule of the drug for the Phase I study based upon efficacy and toxicity
Methodology
EL102 was profiled as both a single agent and in combination with standard of care in xenograft models where efficacy had been demonstrated in vitro. EL102 was administered either daily bid for 28 days, or in cycles of either 3 days or 7 days with a dosing holiday. Tumor volumes and, in some cases, tumor PK were assessed as primary readouts.
An oral formulation of EL102 was developed for clinical usage, and administered bid in both a 14 day dose range finder and subsequently a 28 day cycle to rats and dogs. TK samples were obtained and analysed for both species.
Preliminary data
EL102 demonstrates encouraging anti-tumor efficacy in a number of cell lines in vitro, with low nM IC50 values obtained in both solid and liquid tumor types. Subsequent profiling of EL102 in multiple myeloma patient cells, led to cell kill in primary tumor cells with no effect on the tumor microenvironment, suggesting that multiple myeloma cells may be particularly sensitive to the drug. In addition, mechanism of action studies demonstrates that EL102 is a potent antagonist of several nuclear receptors, (including PR, AR and ERRalpha) and the ADORA3 GPCR. This data, together with the inhibition of HIF1alpha signalling, positions EL102 as a novel anti-cancer agent with activity in tumors which have deregulated key signalling pathways and provides a strategy for subsequent patient stratification in the clinic. Toxicology data in rodents suggests that EL102 is well tolerated at exposure levels which produce an anti-tumor effect in mouse models and support the further clinical development of EL102 in cancer patients in a wide range of other tumor types including multiple myeloma.
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 LB-385. doi:10.1158/1538-7445.AM2011-LB-385