application): The HER2 (erbB2, neu) gene encodes a transmembrane tyrosine protein, a member of the epidermal growth factor receptor family which is amplified and over expressed in nearly 30% of human cancers. HER2 is associated with poor prognosis, chemoresistance, and aggressive and metastatic tumor growth. This year a humanized monoclonal antibody to HER2 received Fast Track Product Status for the treatment of metastatic breast cancer validating HER2 as an effective target for breast cancer treatment. However, problems associated with the use of antibodies as therapeutic agents are well known. Thus a small molecule, non-peptide orally active HER2 antagonist would be a highly desirable potential therapeutic agent. The applicant uses patented and proprietary drug design capabilities to extract 3D-pharmacophore structural information from computationally modeled dynamic protein surfaces and uses this pharmacophore information to prescreen large-scale compound libraries (both commercial and in-house generated virtual combinatorial libraries) for likely drug activity. The goal of Phase I is to identify one or more families of HER2 antagonists using the ATP binding site of the kinase domain and to obtain lead molecule candidate(s) with Ki less than 20 uM. Phase II will include computationally guided synthetic refinement of active lead compounds identified in Phase I.
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