Kinase mutants

Van Holde KE, Zlatanova J, Arents G, Moudrianakis E (1995) Chromatin structure and gene expression (Elign SCR, ed). Oxford University Press, Oxford, ppl-26 Wang Y, Beerman TA, Kowalski D (2001) Antitumor drug adozelesin differentially affects active and silent origins of DNA replication in yeast checkpoint kinase mutants. Cancer Res 61(9) 3787-3794... 

Black, M. E., Newcomb, T. G., Wilson, H. M., and Loeb, L. A. (1996). Creation of drug-specific herpes simplex virus type 1 thymidine kinase mutants for gene therapy. Proc. Natl. Acad. Sci. USA, 93, 3525-3529. 

Munir KM, French DC, Loeb LA (1993) Thymidine kinase mutants obtained by random sequence selection. Proc Natl Acad Sci USA 90 4012-4016... 

Imatinib. Chronic myelogenous leukemia (CML) results from a genetic defect in the hematopoietic stem cells of the bone marrow. Nearly all CML patients possess the Philadelphia chromosome. It results from translocation between chromosomes 9 and 22 of the c-abl protooncogene, leading to the hybrid bcr-abl fusion gene on chromosome 22. The recombinant gene encodes a tyrosine kinase mutant with unregulated (constitutive), enhanced activity that promotes cell proliferation. Imatinib is a tyrosine kinase inhibitor that specifically affects this mutant but also interacts with some other kinases. It can be used orally in Philadelphia chromo-some-positive CML. 

Active Inhibitor-insensitive Kinase Mutants (Orthogonal Protein Kinases)... 

Figure 6.3 Schematic illustration of the generation of inhibitor-insensitive kinase mutants. The interaction of ATP-site competitors with kinase domains has been structurally characterized through the so-called Traxler model [10]. The part of the inhibitor that corresponds to the adenine ring binds to the hinge region of the kinase domain via H bonds. Next to the hinge region are the hydrophobic back pocket and the surface-exposed front pocket, which do not play a role in ATP binding. However, these pockets are extremely critical determinants in inhibitor binding, since the...

The sizes of these panels vary from about 200 kinases at Caliper to over 400 at Ambit. The assay counts include the lipid kinases, mutant kinases and kinases that are available in more than one assay condition (the number of wild type kinases in any of the panels is less than the total). These assay panels enable assessment of broad selectivity and liability information needed for lead and candidate characterization. They also enable broad screening for chemical starting points for kinases across the kinome in parallel. Indeed, we reported doing this in 2008 against the 203 kinases available in the Ambit panel at that time, which will be discussed elsewhere in this review. 

Penner J, Mantey LR, Elgavish S et al. (2006) Influence of UDP-GlcNAc 2-Epimerase/ManNAc kinase mutant proteins on hereditary inclusion body myopathy. Biochemistry AS, 2968-2977. 

Black ME, Kokoris MS, Sabo P. Herpes simplex virus-1 thymidine kinase mutants created by semi-random sequence mutagenesis improve prodrug-medialed tumor cell killing. Cancer Res 2001 61(7) 3022-3026. 

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