Drug kinase inhibitors

Kunkel, E. J., Plavec, L, Nguyen, D., Melrose, J., Rosier, E. S., Kao, L. T., Wang, Y., Hytopoulos, E., Bishop, A. C., Bateman, R., et al. (2004). Rapid structure-activity and selectivity analysis of kinase inhibitors by Bio Map analysis in complex human primary cell-based models. ASSAY Drug Dev. Technol. 2 431-441. 

Akritopoulou-Zanze I (2006) The identification of new protein kinase inhibitors as targets in modern drug discovery. ID rugs 9 481-487... 

Noble ME, Endicott JA, Johnson LN (2004) Protein kinase inhibitors insights into drug design from structure. Science 303 1800-1805... 

Note that application in the particular indications is usually restricted either to patients expressing the target (e.g. trastuzumab, cetuximab, lapatinib, imatinib) and/or after failure of prior therapies (e.g. cetuximab, erlotinib, lapatinib, sutinib, dasatinib). Furthermore, for cancer treatment most tyrosine kinase inhibitors are applied in combination with conventional chemotherapeutic drugs, such as fluorouracil, taxanes, platin-based regimens, anthracylines and irinotecan or radiotherapy. 

Though a large number of small molecule inhibitors against a variety of tyrosine kinases are being developed, the most advanced drugs can be roughly classified as (i) Bcr-Abl/Src family kinase inhibitors, (ii) ErbB inhibitors and (iii) broad spectrum TfCIs with an anti-angiogenic component. 

Dancey J, Sausville EA (2003) Issues and progress with protein kinase inhibitors for cancer treatment. Nat. Rev. Drug Discov. 2 296-313... 

Several other inhibitors of nonreceptor PTKs are currently in development but only a few of them are studied in clinical trials. Noteworthy, Dasatinib does not only inhibit c-Abl, but also potently blocks Src activity, a property that may contribute to its beneficial clinical effects in CML. Other kinase inhibitors being developed that inhibit c-Abl and/or Src are AZD-0530, AP-23994, PD-0183805, SU-6656, and Bosutinib (SKI-606). Furthermore, peptidomimetic SH2 domain inhibitors for Src, such as AP-22408 have been designed that decrease bone resorption and may be promising drugs to treat osteoporosis and other bone diseases, such as Paget s disease and osteolytic bone metastasis. 

There are more than 100 different types of tyrosine kinases present in the body. Sometimes tyrosine kinase inhibitors are referred to as small-molecule inhibitors. Each of the following drugs was developed to block either several or a specific tyrosine kinase. 

Gleevec ) is a tyrosine kinase inhibitor used as first-line therapy in the majority of patients with CML. As a potent tyrosine kinase inhibitor, imatinib inhibits phosphorylation of various proteins involved in cell proliferation. Imatinib works by binding to the ATP-binding pocket of BCR-ABL.7 The drug induces complete hematologic responses in more than 95% of patients and complete cytogenetic responses in about 80% of patients in chronic phase.8 Most patients have traces of the disease when measured by RT-PCR and are not cured of their disease. 

Hartmann, J. T., Haap, M., Kopp, H. G. 8c Lipp, H. P. Tyrosine kinase inhibitors - a review on pharmacology, metabolism and side effects. Curr. Drug Metab. 10, 470-481 (2009). 

As mentioned above, inhibition of adenosine kinase increases extracellular adenosine concentrations. Interest in enhancement of the neuroprotective, antinociceptive, and anti-inflammatory actions of adenosine has encouraged development of systemically applicable adenosine kinase inhibitor drugs. For example, it was found recently that the specific adenosine kinase inhibitor ABT-702, when given intraperitoneally, increases sleep and slow wave EEG activity of rats (Radek et al, 2004), a finding that encourages further research into the hypnogenic effect of this type of drug. 

With the advance of X-ray crystalography and the ability to determine the three dimensional structure of the kinase with the bound inhibitor, drug design has become more precise and rational. The three dimensional structures of a two tyrosine kinases complexed with a kinase inhibitor have already been solved ... 

The unbound fraction of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib has been extensively studied in cancer patients [39]. The drug was found to bind to serum albumin, oq-acid glycoprotein, and red blood cells with a mean unbound fraction of 3.4% which was constant over 28 days of dosing. Unbound fraction ranged from 2.2% to 5.4% and was inversely correlated with pre-treatment levels of oq-acid glycoprotein. 

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