37. Gazit A, Yaish P, Gilon C, Levitzki A. Tyrphostins I: synthesis and biological activity of protein tyrosine kinase inhibitors. 1989 ;32 :2344 -2352
Of all the tyrosine kinase inhibitors the most successful are Gleevec, Iressa and Tarceva. The novel anticancer drug Gleevec/ Glivec/ Imatinib mesylate (Novartis STI571) is a success for CML and c-kit positive metastatic GIST. Gleevec selectively and effectively inhibits the kinase activity of BCR-ABL fusion protein, which is responsible for the constitutive proliferative signaling. It also inhibits TEL-ABL and TEL-PDGFR fusion proteins. STI571 remains bound to the ATP binding cleft of the unphospholrylated (activation loop) Abl, thus establishing extensive contacts with residues lining the cleft and with peptide segments just outside the cleft. A large change in conformation of the nucleotide binding domain is accompanied with the binding of the drug. The binding of STI571 prevents ATP to access the ATP binding cleft and thus inhibits subsequent tyrosine phosphorylation of the substrate [,,] . Iressa is a selective inhibitor of EGF receptor tyrosine kinase in non small cell lung cancer and squamous cell carcinoma  .
Tyrosine kinases are important mediators of the signaling cascade, determining key roles in diverse biological processes like growth, differentiation, metabolism and apoptosis in response to external and internal stimuli. Recent advances have implicated the role of tyrosine kinases in the pathophysiology of cancer. Though their activity is tightly regulated in normal cells, they may acquire transforming functions due to mutation(s), overexpression and autocrine paracrine stimulation, leading to malignancy. Constitutive oncogenic activation in cancer cells can be blocked by selective tyrosine kinase inhibitors and thus considered as a promising approach for innovative genome based therapeutics. The modes of oncogenic activation and the different approaches for tyrosine kinase inhibition, like small molecule inhibitors, monoclonal antibodies, heat shock proteins, immunoconjugates, antisense and peptide drugs are reviewed in light of the important molecules. As angiogenesis is a major event in cancer growth and proliferation, tyrosine kinase inhibitors as a target for anti-angiogenesis can be aptly applied as a new mode of cancer therapy. The review concludes with a discussion on the application of modern techniques and knowledge of the kinome as means to gear up the tyrosine kinase drug discovery process.
The ATP binding intracellular catalytic domain that catalyzes receptor autophosphorylation displays the highest level of conservation between the RTKs. The ATP binding site serves as a docking site for specific binding of cytoplasmic signaling proteins containing Src homology-2 (SH2) and protein tyrosine binding (PTB) domains. These proteins in turn recruit additional effector molecules having SH2, SH3, PTB and Pleckstrin homology (PH) domain. This results in the assembly of signaling complexes to the activated receptor and the membrane and subsequent activation of a cascade of intracellular biochemical signals, which leads to the activation or repression of various subsets of genes and thus defines the biological response to signals. During these processes, receptors migrate within the plasma membrane and are internalized through clathrin-coated invagination, which eventually seal off and forms an endocytic vesicle. The endocytic vesicles fuse with the lysosomes and in the process the receptor and ligand may be degraded by the lysosomal enzymes. The receptors are also recycled in some cases. During the whole process of receptor internalization the ligand receptor complex is dissociated and this results in the termination of the signaling reaction.
T1 - Synthesis and biological activity of a novel class of small molecular weight peptidomimetic competitive inhibitors of protein tyrosine phosphatase 1B