KINASE INHIBITORS

Tyrosine kinase inhibitors (TKIs) are small molecules that are generally designed to fit into the active site of both receptor and non-receptor tyrosine kinases, thus inhibiting the enzymatic (phosphotransferase) function. Since aberrant functioning or overexpressed tyrosine kinases are now known to be the primary cause of many cancers, specific TKIs have become the first-line treatment for certain patient groups (e.g. CML, myelofibrosis, AML, MM). These successful new therapeutics have shown remarkably high response rates for a number of diseases, spurring intense interest in the development of novel TKIs targeting a variety of disease-associated kinases.

However, TKIs are known to have significant myelotoxic liabilities, and most cause some degree of myelosuppression, with neutropenia and thrombocytopenia being the most significant.

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Figure-2

Correlation of in vitro CFC assay results with clinical neutropenia caused by TKIs

We have used a panel of approved therapeutic TKIs as a model system to evaluate the predictiveness of in vitro CFC (colony-forming cell) assays for clinical myelosuppression. Specifically, we tested the ability of the CFU-GM assay to predict the level of clinical neutropenia reported to be caused by these TKIs. Our results demonstrate that the in vitro CFU-GM IC50 values correlated extremely well with reported clinical neutropenia for all TKIs tested.

Our assay services include:

 

    • Evaluating and/or predicting myelotoxic liabilities (including neutropenia, anemia and thrombocytopenia) of new TKIs (single or multiple analogues) in in vitro CFC assays
    • Comparing and ranking the myelotoxic liability of new TKIs against a panel of approved therapeutic TKIs with known levels of clinical neutropenia in our HemoRANK™-TKI assay system (utilizing CFU-GM assays) can predict the level of clinical neutropenia

References

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E. Clarke et. al.,

SOT 2011 Poster Session ‘Stem Cell Toxicology’. 2011 (March 8); Abstract #1172, Poster Board #620.

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E. Clarke et. al.,

SOT 2009 Poster Session ‘Stem Cell Biology & Toxicology’. 2009 (March 18); Abstract #1851, Poster Board #439.