Tyrosine kinase inhibition

EGFR Receptor tyrosine kinase Inhibition of cell proliferation and colony formation decrease of in vivo tumorigenicity... 

RET Receptor tyrosine kinase Inhibition of colony formation... 

D. indicus Gaertn. is known to abound with anthraquinones, but its pharmacological potential remains unexplored to date (20,21). Note that damnacanthal is a common component of the Damnacanthus species. Faltynek et al. made the interesting observation that damnacanthal inhibits the enzymatic activity of tyrosine kinase, which is involved in the propagation of metastases (22). An interesting development from this observation would be to assess the topoisomerase inhibitory activity of the Damnacan-thus species, an activity that could be associated with tyrosine kinase inhibition, hence enormous chemotherapeutic potentials. 

Genistein (116) Isoflavone Genistein (116) Oncology (antitumor) Protein-tyrosine kinase inhibition, antioxidative Phase I/II Astellas, Bausch Lomb 708... 

BMS-354825, which has the generic name of dasatinib, entered Phase II clinical trials in December 2004 under the START (Src/Abl Tyrosine kinase inhibition Activity Research Trial) program [ 144-147]. Dosing was initiated at 70 mg twice daily with the option of increasing the dose to 90 or 100 mg or reducing the dose to 40 or 50 mg, depending on low response or toxicity. As part of the Phase I and II trials, patients were assessed for the presence of Bcr-Abl mutations prior to treatment with BMS-354825. In a study at UCLA,... 

Ferry DR, Smith A, Malkhandi J, F e DW, deTakats PG, Anderson D, Baker J, Kerr DJ (1996) Phase 1 clinical trial of the flavonoid quercetin pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin Cancer Res 2 659-668 Findik D, Song Q, Hidaka H, Lavin M (1995) Protein kinase A inhibitors enhance radiation-induced apoptosis. J Cell Biochem 57 12-21 Fine RL, Patel J, Chabner BA (1988) Phorbol esters induce multidrug resistance in human breast cancer cells. Proc Natl Acad Sci USA, 85 582-586 Finkenzeller G, Marme D, Hug H (1992) Inducible overexpression of human protein kinase C in NIH 3T3 fibroblasts results in growth abnormalities. Cell Signall 4 163-177... 

Force, T, Krause, D.S. andVanEtten, R.A. (2007) Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nature Reviews. Cancer, 7, 332-344. 

Ferry, D.R., Smith, A., Malkhandi, J., Fyfe, D.W., deTakats, P.G., Anderson, D., Baker, J., and Kerr, D.J., Phase I clinical trial of the flavonoid quercetin pharmacokinetics and evidence for in vivo tyrosine kinase inhibition, Clin. Cancer Res., 2, 659, 1996. 

Four minor metabolites, psammaplins B-D (503-505) and presammaplin A (506) were isolated from Psammaplysilla purpurea, in addition to psammaplin A (500). Psammaplin B (503) is a thiocyanate bromotyrosine derivative, while psammaplin C (502) is a sulfanamide. Psammaplin D (505) displayed antimicrobial activity and mild tyrosine kinase inhibition [429]. The psammaplins Ai (507) and A2 (508) and aplysinellins A (509) and B (510) were isolated from Aplysinella rhax from both Pohnpei and Palau. These compounds inhibit famesyl protein transferase and leucine aminopeptidase [430]. Another sample of A. rhax from the Great Barrier Reef, Australia contained psammaplin A 11 -sulfate (511) and bisaprasin ll -sulfate (512), both of which inhibited [3H]-l,3-dipropyl-8-cyclopentylxanthine binding to rat brain adenosine Ai receptors [431]. 

ERK1/2 activation by Ang II, which can be blocked by PLC inhibition, intracellular Ca2+ chelation, and tyrosine kinase inhibition, eventually proceeds through a Ras-dependent pathway (Eguchi et al. 1996). One intermediate tyrosine kinase... 

Figure 14.1 Superposed receptor tyrosine kinases inhibited by members of the nakijiquinone-based library. Yellow Tie-2 RTK (homology model) red VEGFR-3 (homology model) blue IGF1R with bound ATP analog (X-ray structure).

A. Levitzki and A. Gazit. Tyrosine kinase inhibition An approach to drug development. Science, 267,... 

Tyrosine phosphorylation of three MAPK subgroups (ERKl, ERK2 and P38) stimulated by LPS was inhibited by 28 in a dose dependent manner. It has been proposed that tyrosine kinase inhibition may occur through conjugation between the a-methylenebutyrolactone in parthenolide and the -SH group of target proteins [85]. 

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