BACKGROUND:  Tyrosine kinases (TKs) are a diverse family of highly regulated enzymes that, upon activation, phosphorylate target proteins on the amino acid tyrosine. TKs are involved in many cellular functions such as cell division and cell proliferation, as well as in several diseases including cancer and diabetes. Active site TK inhibitors, such as Imatinib (Gleevac) and Dasatinib (Sprycel), are the primary treatment options for chronic myelogenous leukemia (CML) and some other malignancies. Unfortunately, TK point mutations can prevent the inhibitors from binding and lead to drug resistance and disease relapse. Thus, an alternative method of inhibiting TKs would lead to treatment options for TK inhibitor-resistant patients and should reduce the rate of resistance to TK inhibitors in patients beginning therapy.

INNOVATION:  Researchers at UCLA have developed a high throughput screen (Z factor > 0.5) to test for novel tyrosine kinase (TK) inhibitors that do not target the TK active site. The assay can be used to identify compounds that inhibit both normal and oncogenic forms of TKs by blocking their activation by regulatory proteins. This assay is especially useful in the field of chronic myeloid leukemia (CML) treatment, because it can detect compounds that will inhibit the interaction of BCR-ABL1 (the oncogenic TK involved in CML) and its regulator protein RIN1.

POTENTIAL APPLICATIONS 

• Identify next generation kinase inhibitors active against imatinib-resistant variants of BCR-ABL to treat CML
• High throughput assay to detect non-catalytic site inhibitors of tyrosine kinases
• Assay to detect inhibitors of any tyrosine kinase and its regulator protein

ADVANTAGES

• Assay designed to detect compounds that block activation of a tyrosine kinase by regulatory proteins
• Robust high throughput assay with Z factor > 0.5

DEVELOPMENT-TO-DATE:  This assay has been validated with the tyrosine kinase ABL and its physiological regulator RIN1.

Reference: UCLA Case No. 2009-076