Our long term objective is to generate and test lead compounds to be evaluated in future clinical trails for cancer treatment through the identification of antagonists of neuregulin-erB signalling. Our approach is based on a novel, untapped component of this signalling system - the interaction of neuregulins with glycosaminoglycans (GAGs; e.g., heparan sulfate proteoglycans), and hence we use a proprietary screening technology to identify compounds that block this target. In preliminary studies we have characterized the essential nature of neuregulin-GAG interactions for growth factor signalling, have developed and tested isonitrile-based combinatorial chemistry, and have formatted a high-throughput binding assay to identify potential antagonists. In our initial use of this technology 17 candidates have been identified from a screen of 3,824 novel compounds. All potential leads identified biochemically will validated wit in vitro studies and tested for selectivity against a panel of heparin-binding growth factors. The most promising lead compounds will be advanced into Phase II efforts where the focus will be on testing therapeutic efficacy in animal models of tumor establishment and progression and on lead optimization. PROPOSED COMMERCIAL APPLICATION: Neuregulin antagonists may be useful in treating a fairly broad spectrum of cancers. The primary intended therapeutic targets include tumors of glial cell origin, such as Schwannomas and central neurofibromas, adenocarcinomas of breast, ovary and stomach, and melanomas.
Thesaurus Terms:antineoplastic, chemical binding, chemical synthesis, neurotrophic factor heparin, inhibitor /antagonist, suramin cell line, chemical registry /resource, high performance liquid chromatography, neoplastic cellNational Cancer Institute (NCI)
