C-Kit kinases inhibitors

Fernandez A, Sanguino A, Peng Z et al (2007) An anticancer C-kit kinase inhibitor is reengineered to make it more active and less cardiotoxic. J Clin Invest 117 4044-4054... 

Sorafenib/BAY 43-9006 RAF, VEGFR, PDGFR, c-Kit Kinase inhibitor Phase III, Kidney Cancer... 

Fig. 8.7 (a) In vitro phosphorylation inhibition assay for Abl enzyme in the presence of WBZ 4 (squares) or imatinib (triangles). Active recombinant Abl enzyme (1 (Jig/ml) and its substrate (Abl-tide, 1 p.g/ml) were incubated for 1 h at 37°C in the presence of various WBZ 4 or imatinib concentrations. ATP (100 nM) was added to the reaction mixture. Phosphorylation of Abl-tide peptide was detected by incubation in consecutive order with antirabbit phospho-Abl-tide antibody and antirabbit horseradish peroxidase (HRP) antibody. Phosphorylation of the substrate was quantified as absorbance units (AU) by spectrophotometry at 450 nm. Values obtained with the enzyme without the inhibitors (WBZ 4 or imatinib) were assumed to be 100% phosphorylation and were compared to the values obtained with the addition of the inhibitors, (b) In vitro phosphorylation inhibition assay for C-Kit in the presence of WBZ 4 (squares) or imatinib (triangles). Active recombinant C-Kit kinase (25 ng/ml) and its substrate poly (Glu4-Tyr, 150 nM) were... 

STI 571 <322> (<322>, a phenylaminopyrimidine derivative, a potent inhibitor of the Abl tyrosine kinase, PDGFR kinases and c-Kit tyrosine kinases [705] <322> designed to inhibit ABL and BCR-ABL tyrosine kinases, inhibition through competitive ATP-binding pocket interactions [706] <322> use un second-line therapy of small-cell lung cancer, inhibits c-kit kinase, resulting in an metabolic change of tumor cells [706]) [705, 706]... 

Akin C. Brockow K. D Ambrosio C. et al Effects of tyrosine kinase inhibitor SXI571 on human mast cells bearing wild-type or mutated c-kit. Exp Hem-atol 2003 31 686-692. 

Imatinib Mesylate (Gleevec) Tyrosine kinase inhibitor bcr-abl, c-kit Chronic myelogenous leukemia Hematologic and cytogenetic response rate. Phase III GIST ... 

AG 1024 has been extensively studied as an IGFR inhibitor [70] and is a substrate competitive inhibitor of this kinase [71]. AG1024 also inhibits other kinases including c-Kit [72]. Additional studies will be needed, including a direct measurement of Abl activity and possible subsequent testing against the imatinib resistant Abl point mutations, to ascertain the possible therapeutic utility of AG 1024. 

Imatinib (STI571) is an inhibitor of the tyrosine kinase domain of the Bcr-Abl oncoprotein and prevents the phosphorylation of the kinase substrate by ATP. It is indicated for the treatment of chronic myelogenous leukemia (CML), a pluripotent hematopoietic stem cell disorder characterized by the t(9 22) Philadelphia chromosomal translocation. This translocation results in the Bcr-Abl fusion protein, the causative agent in CML, and is present in up to 95% of patients with this disease. This agent inhibits other activated receptor tyrosine kinases for platelet-derived growth factor receptor (PDGFR), stem cell factor (SCF), and c-kit. 

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