Abstract B238: Novel imidazo[1,2-a]pyridines as inhibitors of the IGF-1R tyrosine kinase.

Abstract

Abstract The Insulin-like Growth Factor-1 Receptor (IGF-1R) is a receptor tyrosine kinase which plays an important role in cancer by promoting proliferation and survival through activation of the Ras/Raf/MAPK and PI3K/Akt signaling pathways. Deregulation of the IGF-1R axis has been reported in a variety of solid cancers and occurs by overexpression of either the receptor or its ligands (IGF-1 and IGF-2) or by down-regulation of IGF binding proteins (in particular IGFBP3). Therapeutic approaches to inhibit IGF-1R signaling include antibodies targeting the receptor and small molecule inhibitors of the tyrosine kinase. The latter strategy offers a potential advantage by simultaneously inhibiting the closely related Insulin Receptor A (IR-A) tyrosine kinase. Indeed, IR-A can drive tumor growth in some cancer cell lines and has been suggested has a potential escape mechanism for IGF-1R inhibition. Following a cell based high throughput screening, we have identified a series of imidazo[1,2-a]pyridines inhibiting the IGF-1R kinase. Although hit compounds carried a significant activity against CDK2, modifications of the aniline part has led to more potent and selective inhibitors. We selected 1-[4-[4-[(5-chloro-4-imidazo[1,2-a]pyridin-3-yl-pyrimidin-2-yl)amino]-3-methoxy-phenyl]piperazin-1-yl]ethanone (5) as a lead compound having good pharmacokinetics in pre-clinical species. Compound (5) displays a dual inhibition of IGF-1R and the insulin receptor tyrosine kinase as measured in biochemical assays as well as in cellular auto-phosphorylation assays. Structure-activity relationship around (5) is described for IGF-1R inhibition as well as for the hERG ion channel. Compound (5) has been assessed in an in vivo efficacy model based on the NIH 3T3 fibroblast cell line transfected to express human IGF-1R and IGF1 ligand. In contrast to the non-transfected parent line, this cell line rapidly grows as a sub-cutaneous xenograft in nude mouse, thus providing a suitable model to measure anti-IGF-1R pharmacology by tumor growth inhibition. The high expression of IGF-1R also enables the generation of good quality PD data using receptor phosphorylation as an endpoint. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B238.