Imatinib inhibitor selectivity

Inhibition of hematopoietic growth factors Imatinib (Glivec ) is applied to treat chronic myeloid leukemia in Philadelphia-chromosome positive patients. In these patients, translocation of parts of chromosomes 9 and 22 results in the expression of a fusion protein with increased tyrosine kinase activity, called Bcr-Abl. Imatinib is a small Mw inhibitor selective for the tyrosine kinase activity of Bcr-Abl. Thereby, it inhibits the Bcr-Abl induced cell cycle progression and the uncontrolled proliferation of tumor cells. 

Nilotinib is a phenylaminopyrimidine structurally related to imatinib (Glivec) . It is a signal transduction inhibitor that potently and selectively inhibits tyrosine kinases. It was developed (Phase 11/111) for treatment of leukemias. ... 

Figure 2.19 The lead structure 67 is a protein kinase C (PKC) inhibitor prototype. Whereas the optimized analog 68 is a strong PKC inhibitor, amides 69 also inhibit tyrosine kinases like the bcr-abl kinase. Introduction of a methyl group, to form 70, abolishes the PKC activity. The optimized analog imatinib 71 (Gleevec , Glivec , Novartis) is a highly selective bcr-abl tyrosine kinase inhibitor.

In order to enhance affinity and selectivity for Brc-Abl, we modified the inhibitor methylating at positions I and II (Fig. 7.5d). The synthesis of the wrapping prototype recapitulates imatinib synthesis [38], as described in [39], To test whether the specificity and affinity for Brc-Abl improved, we conducted a spectrophotometric kinetic assay to measure the phosphorylation rate of peptide substrates in the presence of the kinase inhibitor at different concentrations. This assay couples production of adenosine diphosphate (ADP), the byproduct of downstream phosphorylation, with the concurrent detectable oxidation of reduced nicotinamide adenosine dinucleotide (NADH). The oxidation results upon transfer of phosphate from PEP (phospho-enolpyruvate) to ADP followed by the NADH-mediated reduction of PEP to lactate. Thus, phosphorylation activity is monitored by the decrease in 340 nm absorbance due to the oxidative conversion NADH->-NAD+ [34, 39]. 

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