SBIR-STTR Award

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.

HER2 is a transmembrane receptor tyrosine kinase overexpressed and amplified in nearly 30 percent of cancers. It is associated with poor prognosis, chemoresistance, and aggressive and metastatic tumor growth. Herceptin, a humanized monoclonal antibody to HER2, is currently available for 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. Structural Bioinformatics Inc. used patented and proprietary drug design capabilities to extract 3D-pharmacophore structural information from computationally modeled dynamic protein HER2 kinase and used the pharmacophore information from this model to prescreen large-scale compound libraries for inhibitors of HER2 activity. Nine compounds showing IC50's < 20 uM in functional assays were obtained. The goal of Phase II is to perform computationally guided synthetic optimization and refinement of active lead compounds identified in Phase I and to discover selective and potent drug candidates active in various HER2 preclinical tumor models for advancement into clinical development. The long-term goal of the project is to develop a non-peptide potent and selective Herceptin-like drug for the treatment and prophylaxis of HER2 oncogene-mediated transformation, tumorigenesis, and metastasis