Tyrphostins

Keywords Tyrphostins, Protein tyrosine, Kinases, JAK-2 EGF, PDGF BCR-ABL, Psoriasis, Papilloma, Restenosis, Leukemia, Lymphoma... 

The Synergistic Action of Tyrphostins with Cytotoxic Agents... 

It was initially argued that the best potential PTK inhibitors would be compounds that compete for the substrate in the kinase binding domain. It was argued that such compounds would be less toxic than ATP mimics since they bind to those domains at the kinase site that are less conserved than the substrate binding domains. Indeed tyrphostins like AG 490 which blocks Jak-2 [10] and AG 556 which possesses anti-inflammatory properties have been shown to be highly non-toxic in vivo [34-37]. 

Over the past decade, however, the PTK inhibitors favored by most investigators have been ATP mimics that compete with ATP at the binding site. Most of the compounds depicted in Table 2 are ATP mimics with the exception of the tyrphostins developed by us. In the case of tyrphostins one can indeed classify compounds which compete with ATP, compounds which compete with the substrate and bisubstrate inhibitors which compete with the substrate and ATP simultaneously [18]. Compounds can also be identified that act as mixed competitive inhibitors which bind simultaneously with ATP and/or substrate but decrease the affinity of ATP and the substrate to their respective sites [18,22]. Among the tyrphostins all classes of compounds can be identified [18] but the real question is which of these is preferable for clinical development. 

A number of families of PTK inhibitors (tyrphostins) have shown efficacy in tissue culture as well as in vivo. A significant number of benzene malono nitriles (BMNs), which belong to the founding family of PTK inhibitors were found to possess biological activity. These include AG 490, AG 126 and AG 556 for which promising in vivo data already exist [10,11,34-37]. 

The combination of tyrphostins with cytotoxic drugs can be followed by immunotherapy in order to eliminate residual disease. Though such combinations have not yet been examined, the combination of AG 490 and IL-12 against IL-6 dependent multiple myeloma recently showed impressive tumor suppressive effects [54], suggesting that the general idea may indeed be correct. 

Fishbein I, Chorny M, Banai S, et al. Formulation and delivery mode affect disposition and activity of tyrphostin-loaded nanoparticles in the rat carotid model. Arterioscler Thromb Vase Biol 2001 21 1434-1439. 

Protein Kinase Inhibitors Pseudosubstrate-based peptide inhibitors, 201, 287 utilization of the inhibitor protein of adenosine cyclic monophosphate-dependent protein kinase, and peptides derived from it, as tools to study adenosine cyclic monophosphate-mediated cellular processes, 201, 304 use of sphingosine as inhibitor of protein kinase C, 201, 316 properties and use of H-series compounds as protein kinase inhibitors, 201, 328 use and specificity of staurosporine, UCN-01, and calphostin C as protein kinase inhibitors, 201, 340 inhibition of protein-tyrosine kinases by tyrphostins, 201, 347 use and specificity of genistein as inhibitor of protein-tyrosine kinases, 201, 362 use and selectivity of herbimycin a as inhibitor of protein-tyrosine kinases,... 

Although less explored, drug discovery efforts have also been directed to modulate IGF-IR kinase activity by compounds that do not necessarily interact with the ATP-binding cleft. Initial attempts to inhibit IGF-IR enzymatic activity with non-ATP competitive inhibitors resulted in the identification of several tyrphostin-type compounds (e.g., compound 4, Fig. 2) that showed weak activity in blocking IGF-IR autophosphorylation (IC50 7-13 p.M), but... 

In 1994, the tyrphostin AG957 (9) was identified as an inhibitor of Bcr-Abl that blocked the proliferation of K562 cells [64] (Scheme 4). Solubility and... 

Mazumder A, Gazit A, Levitzki A, Nicklaus M, Yung J, Kohlhagen G, Pommier Y. Effects of tyrphostins, protein kinase inhibitors, on human immunodeficiency virus type 1 integrase. Biochem 1995 34 15111-15122. 

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