Abstract 3247: Design and development of ICT2700: A proof-of-concept agent demonstrating the therapeutic potential in targeting cytochromes P450 for tumor-selective activation
Authors: Pors Klaus , Shnyder Steven D. , Sharma Alok , Rigby Alan C. , Grant Marianne A. , Sutherland Mark , Sheldrake Helen M. , Gill Jason , Loadman Paul M. , Searcey Mark , Patterson Laurence H. 
Published: June 2012

The cytochromes P450 (CYPs) are a superfamily of mixed function oxidases that are unique in their ability to oxidize xenobiotics, but under hypoxic conditions also can reduce certain chemical functionalities. There is now growing evidence that CYP1A1, 1B1, 2J2, 2S1 and 2W1 are expressed and in some instances over-expressed in many human tumour types. The presence of certain CYPs may reflect a resistance mechanism by diminishing the pharmacological activity of anticancer drugs whilst specific CYPs can also modulate cell proliferation by the formation or conversion of endogenous signalling molecules. Among several pharmacophores, we have identified the aryl-based chloromethylindolines as a novel class of agent, which lend themselves to being great candidates for use in prodrug strategies. We have synthesised and biologically evaluated several libraries of chloromethylindolines and have shown them to be activated in several CYP1A1 expressing cell lines including the human variants EJ-138, MCF-7 and RT112. We have demonstrated using ICT2700 as a Proof of Concept (PoC) compound that incubation with the CYP1 inhibitor alpha-naphthoflavone leads to loss of cytotoxic activity, which underpins the involvement of CYP1A1-mediated activation in the cytotoxicity of the chloromethylindoline pharmacophores. In vivo, we have used the CHO cell line since it does not naturally express significant levels of drug metabolising CYPs whilst accommodating stably transfected CYP1A1 as an enriched variant. ICT2700 was administered i.p. to immunodeficient mice bearing subcutaneous CHOwt and CHO1A1 xenografts at its max. deliverable dose, 150mgkg-1 and at a third of this dose (50mgkg-1). A clear dose-response relationship was evident with significant tumor growth delays seen for both the 150mgkg-1 (%T/C = 300%; p&lt;0.01) and 50mgkg-1 (%T/C = 167%; p&lt;0.05) groups compared with the control group. Significantly, negligible toxicity with weight loss for both treatments were well within normal limits (p&lt;0.01 for both doses). LC-MS of the CYP1A1 expressing xenograft tissue revealed the presence of a metabolite, which upon further NMR analysis revealed high affinity for DNA. The significance of this PoC study lies in the potential to use CYPs naturally overexpressed in tumour tissue as targets to ensure selective chemotherapy. This work also promises the development of a platform technology whereby the metabolic activation of a selected chloromethylindoline can be matched to a specific CYP. As such, our approach will not only greatly improve the therapeutic index of antiproliferative chemotherapy by circumventing or minimising off-target side effects in normal tissue but also addresses the promise of patient specific therapy.

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 3247. doi:10.1158/1538-7445.AM2011-3247