Clinical Implications

Differences in rates of onset of inhibition between compounds can suggest differences in molecular mechanism. Compounds that bind to rare forms of the kinase have slower on rates than those that bind abundant forms. This is seen with both DFG-out (p38 and BRAF)13 and C-helix-out (EGFR) conformations.15 Compounds with slow on rates must have slow off rates relative to equipotent fast binders. These slow off rates give extended drug-target residence times, which can have clinical implications (see Section 4.4.2.4). 

For closely related, rapidly reversible inhibitors following the same mechanism against the same kinase, it may be anticipated that potency in vitro may 

It is difficult to deconvolute how kinase inhibitor binding mode has implications in the clinic. In general, selectivity tends to increase in the order (i) purine site, (ii) selectivity pocket, and (iii) allosteric site. The ability to overcome resistance mutations in cancer therapy tends to be inversely related to this selectivity pattern. Accordingly, allosteric kinase inhibition may become a preferred mechanism for clinical indications other than cancer. 

A slow on rate may compromise activity in vivo, because some of the administered drug could be cleared from the body before binding to the target protein. The association rate in vivo is likely to be slower than that in vitro due to competition by ATP and ADP, and depletion of free drug by nonspecific binding to plasma proteins. 

It has been estimated that around 30% of the enzyme inhibitors used as drugs have a mechanism that includes covalent bond formation.60 This approach has been used in kinase drug discovery in attempts to overcome the competition by ATP and ADP in vivo. However, clinical compounds such as Cl-1033 and HKI-272 were dose-limited by diarrhoea and skin rash linked with inhibition of the target protein, EGFR-TK, outside the tumour.61 Recent work has 

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What are the clinical implications of these interactions How should they be managed ... 

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Lastly, Llerena etal. (2004) compared the CYP2C9 polymorphisms 1, 2, 3, 4, 5, and 6 in Mexican Americans (n = 98) and Spanish subjects (n = 102). Lower frequencies of the variant CYP2C9 2, one of two alleles reported to have altered catalytic activity, were found among the Mexican Americans. Since no phenotypic comparisons were conducted in this study, the clinical implications remain unclear. The authors suggest the need for further studies to assess whether the drug metabolism of medications such as warfarin maybe affected in this population. 

The specific research questions that have important clinical implications include the following ... 

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The extensive genetic heterogeneity of HCV has important diagnostic and clinical implications. 

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