phosphorylate a variety of substrates involved in a many cellular aspects of transformation from cytoskeletal changes to cell cycle-dependent gene transcription. Timely expression of heteroprotein complexes is critical for a mammalian cell, such as S-phase and M-phase cell cycle promoting factors composed of cyclin-dependent kinases (CDKs) and regulatory cyclins. They initiate M- and S-phase progression by phosphorylating transcription factors, which in turn drive the expression of cell cycle machinery. Pertubations in the expression in some aspect of these regulatory heteroprotein complexes are the hallmark of almost every form of cancer. *, PTMs of a signaling protein that have become a focus of novel therapeutic modalities.

doi:10.1201/9780203910696-43

Chapter

phosphorylate a variety of substrates involved in a many cellular aspects of transformation from cytoskeletal changes to cell cycle-dependent gene transcription. Timely expression of heteroprotein complexes is critical for a mammalian cell, such as S-phase and M-phase cell cycle promoting factors composed of cyclin-dependent kinases (CDKs) and regulatory cyclins. They initiate M- and S-phase progression by phosphorylating transcription factors, which in turn drive the expression of cell cycle machinery. Pertubations in the expression in some aspect of these regulatory heteroprotein complexes are the hallmark of almost every form of cancer. *, PTMs of a signaling protein that have become a focus of novel therapeutic modalities.

Chapter

phosphorylate a variety of substrates involved in a many cellular aspects of transformation from cytoskeletal changes to cell cycle-dependent gene transcription. Timely expression of heteroprotein complexes is critical for a mammalian cell, such as S-phase and M-phase cell cycle promoting factors composed of cyclin-dependent kinases (CDKs) and regulatory cyclins. They initiate M- and S-phase progression by phosphorylating transcription factors, which in turn drive the expression of cell cycle machinery. Pertubations in the expression in some aspect of these regulatory heteroprotein complexes are the hallmark of almost every form of cancer. *, PTMs of a signaling protein that have become a focus of novel therapeutic modalities.

ABSTRACT

Initial emphasis in the development of small-molecule protein kinase inhibitors focused on modulating catalytic activity directly. However, homology among the catalytic ATP binding site of hundreds of protein kinases active in a mammalian cell at any given time severely limits the degree of selectivity attainable. A strategy to overcome this has been illustrated by recently developed MEK1 kinase inhibitors that appear to act through an allosteric mechanism of inhibition. This novel class of MEK1 inhibitors display very good toxicity profiles, suggestive of a high degree of selectivity [22]. However, the MAPK signal pathway plays an important role in normal cell signaling for the immune response and neuronal functions, mandating thorough validation in vitro and in vivo [23]. Such validation studies increase the knowledge about the behavior of the small-molecule inhibitor in a complex biological system and may lead to label extension for completely different indications. For example, the MEK1 kinase inhibitors are now being evaluated for their ability to reduce postischemic brain injury [24].