Different signaling cascades. The F Observed ability of the HER2 protein on the form heterodimers may be explained Ren, why overexpression of HER2, the ligand is independent Independent dimerization is associated with a poor prognosis. The activation of EGF-R or ErbB BIBR 1532 BIBR 1532 Telomerase inhibitor has been shown to stimulate cell proliferation, the secretion of angiogenic factors such as VEGF and induce interleukin-8 in order to reduce apoptosis, and receives Ht motility t. Because of his involvement in the development and progression of many human tumors, including breast, lung, C Lon, ovarian, prostate and head and neck, was the EGF-R system as a target weight Drug Discovery hlt prototype. This is supported by the fact that the tyrosine kinase inhibitors are currently five EGF R in the clinical development, three quinazoline-type, an irreversible inhibitor, PKI166 and compounded pyrrolopyrimidine.
2.2.2. PKI166 pyrrolopyrimidines were identified as lead frames by sampling and were then optimized by a pharmacophore model of R ATP-binding site of the GEF. This led to the discovery of PKI166, a potent inhibitor of EGF-R and its two dual tyrosine kinase activity Th, with a reasonable Ma selectivity to t with respect to the inhibition of tyrosine and other Ser / Thr kinase. PKI166 also inhibited activated autophosphorylation of the EGF ligand and R HER 2, and the growth of cell lines EGFdependent, such as BALB keratinocytes, EGF R overexpressing cells A431, NCI H596 cells, additionally Tzlich to overexpression of the HER2 SK BR 3 and BT cell lines 474 . As shown in Fig.
7, inhibition of cell proliferation after exposure entered against A431 cells PKI166 Born in the induction of apoptosis, as determined by laser scanning cytometry. In addition, the antiproliferative activity of t and in vivo Antitumoraktivit t PKI166 were closely fits with the expression of EGF R and / or HER2. In addition, the combination with gemcitabine was well tolerated and showed PKI166 Antitumoraktivit t in metastatic and anti-EGF-R system is a dependent Independent orthotopic model of pancreatic cancer that was more than either drug alone. The use of multiple methods has been shown PKI166, a completely Requests reference requests getting and sustained inhibition of EGF-stimulated EGF-R in vivo autophosphorylationtumors produce.
The antitumor activity of t in vivo can PKI166 in part by the inhibition of angiogenesis mediated induced by the tumor, such as significant reduction in VEGF and IL-8 correlates with a significant decrease of the vessel Dense and shown Erh Increase of apoptosis of endothelial cells in tumors. Based on the current pr Clinical data, should be active against tumors with PKI166 overexpression, or dysfunctional, EGF, and HER2 R. PKI166 is currently in Phase I trials. 2.3. STI571 2.3.1. Bcr Abl leukemia Chemistry and myelo The CML is a chronic h Dermatological stem cell proliferation by over his Marked myelo-owned Of. The hallmark of CML is the Philadelphia chromosome, which in almost all the F Cases of CML and in 20-30% of F Ll of acute lymphoblastic leukemia Chemistry is found Adults. A balanced reciprocal translocation between chromosomes 9 and 22 to replace the first exon of c abl gene sequences Bcr, resulting in the generation of the different melting points Bcr Abl