Office of Technology Transfer – University of Michigan

Dual Inhibitors of Lipid and Receptor Tyrosine Kinases

Technology #6144

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Researchers
Christopher Emil Whitehead
Managed By
Tiefei Dong
Senior Licensing Specialist, Life Sciences 734-763-5332
Patent Protection
US Patent Pending

Dual inhibitors of lipid and receptor tyrosine kinase

A potential solution to address the limitations of combination therapy is to develop a single agent with a dual function of targeting epidermal growth factor receptor (EGFR) and the downstream, bypass PI3 Kinase pathway that supports tumor growth. Although tyrosine kinase and lipid kinase lack significant sequence similarity, they have similar ATP binding motifs and two-lobed structure of their kinase domain. Given this poor structural similarity of protein and lipid kinases, there is limited overlap in the activity of known tyrosine and lipid kinase inhibitors. Using X-ray crystallography and structure-activity relationships derived from known EGFR and PI3K inhibitors, active and highly selective cores common to both EGFR and PI3KC were identified. Based on two common cores, four small molecule compounds have been synthesized with high potency against EGFR and PI3K (PI3Ka IC50 = 26 nM, EGFR IC50 = 342 nM), and blocked AKT phosphorylation in cancer cells. These compounds that can inhibit both PI3K and EGFR may have important therapeutic value in resistant cancers with overexpression of EGFR and/or activation of PI3K/AKT pathway.

Limitations in the use of combination therapy to target EGFR activity in cancer

EGFR is expressed in various malignancies including gliomas, and carcinoma of the lung, colon, head and neck, pancreas, ovary breast, bladder and kidney. EGFR belongs to the ERBB family of transmembrane tyrosine kinase receptors that relay growth signals from the cell membrane into the nucleus to initiate cellular responses. Ligand binding to EGFR triggers homo- or heterodimerization with other ERBB receptors, activation of the tyrosine kinase domain which leads to receptor autophosphorylation at tyrosine residues, and activation of downstream pathways that activate various transcription factors that ultimately drive tumor cell proliferation, angiogenesis, metastasis and impairs apoptosis. Therapies that target the EGFR pathway are used to treat various cancers. Erlotinib and gefitinib are small molecule compounds that inhibit the EGFR tyrosine kinase domain by competitively binding with the site that binds ATP, the phosphate donor in kinase reactions. Monoclonal antibodies cetuximab and panitumumab block ligand-binding to the extracellular domain, promote receptor internalization and mediate antibody and complement-mediated cytotoxicity. Although these EGFR inhibitors have demonstrated benefits, not all cancer patients respond to the treatment, or only have a temporary response with median duration of 10-12 months until they eventually develop resistance. One of the mechanisms of resistance to existing anti EGFR therapies is attributed to activation of bypass signaling pathways. One of the downstream effector signaling pathways activated by EGFR and mutated in 12% of human cancers is the phosphatidylinositol 3-kinase- (PI3K)-protein kinase B (AKT) pathway. Ligand binding to EGFR activates the lipid kinase PI3K which phosphorylates the lipid PI(3,4)P(PIP2) to produce PI(3,4,5)P(PIP3), which then recruits PDK1 to the plasma membrane. PDK1 phosphorylates and activates AKT which regulates various cellular processes that promote tumor growth. The lipid phosphatase, PTEN, commonly mutated or lost in tumors, dephosporylates PIP3, leading to a reduction in PIP3 levels and concomitant decrease in AKT activity. Thus, active PI3K signaling that persists with EGFR inhibition blocks apoptosis or decreased cellular proliferation that is normally mediated by EGFR inhibitors. Combination therapy using multiple EGFR inhibitors, or a combination of an EGFR inhibitor with a drug that targets a bypass-signaling pathway is being developed to combat resistance in EGFR dependent tumors. However, none of the currently used combination of EGFR inhibitors have been very effective clinically. A majority of kinase inhibitors are taken daily and administered at a dose that is based on toxicity and not target inhibition. Therefore, there is an increased likelihood that combination therapies will be highly toxic and the tolerable doses of each agent used in the combination may be suboptimal for target inhibition.

Applications

  • Dual inhibitor of EGFR and PI3K for cancer therapy
  • In vitro inhibitor of EGFR and PI3K for use in research purposes

Advantages

  • Novel dual inhibitor of EGFR and PI3K
  • Improved cytotoxic profile and target inhibition over combination therapy