SECTORS clinical lead EKB 569, 2, the LY2109761 clinical study of lung cancer and non-small cell carcinomas of the c Lon registered. Both HKI, 272 and 569 irreversible EKB-receptor tyrosine kinase inhibitors of the ErbB family members. Especially with the development of these services, we targeted second receptor kinases epidermal growth factor receptor and human epidermal growth factor These receptor tyrosine kinases have an extracellular Ren ligand-binding Dom ne, a single membrane-spanning region and an intracellular NEN Re tyrosine kinase and regulatory Dom. HKI 272 and 569 inhibit the function of EKB-kinase Dom NEN these proteins to form a covalent interaction with a conserved cysteine, Cys 773 and Cys 805 1 to EGFR and HER second The deregulation of these kinases growth factor receptors by overexpression or mutation was associated with a number of cancers in context. An inhibitor site as it was with ATP and tyrphostin weight hlt To represent the tyrosine residue of a protein substrate. Are both H halves To a polar group such as a salicylate-modification, which developed to mimic the triphosphate of ATP and it was assumed that the F Have been ability, connected to coordinate with the magnesium atom of the active site. Basically, these inhibitors were con We act as bisubstrate inhibitors. Other groups were one Bisubstrate adopt similar approach. In retrospect, this approach seems to de novo rather ambitious, although he gave inhibitors with IC50 values in the low to lMrange EGFR in full length Inhibit length enzyme. Results and discussion series 4-kinase inhibitor anilinoquinazoline ErbB Although maximize our efforts, our series of inhibitors bisubstrate were traveling, we became aware of an inhibitor, which shone through the Parke Davis group, reported that at the time, remarkable biological properties have. The compound was called PD153035 and is a derivative of quinazoline 3 pretty simple. The compound has been reported that an ATP-competitive inhibitor of EGFR kinase lie with an IC 50 in subnanomolar.
In addition, the compound is a potent inhibitor of the growth of EGFR is dependent- Ngigen cell lines. As it turned out, was the group Parke Davis is not the only group that discovered this promising series of inhibitors were considered by Council Dissemination of a given patent application Zeneca. We then immediately our attention to the study of structure-activity Ts-relationships of this series, based on our present knowledge of bisubstrate inhibitors, because the compounds in this new series were less complex and st More strongly than our previous inhibitors. It goes Flammable, if we start working with this series of quinazoline derivatives, we have our own region, to see the operation. Back in the draft we had our first homology model of the kinase-Dom Ne of the EGFR Built similar to the model specified. On inspection of this model showed that it is two cysteine residues in the region of ATP binding to the active site, 751 Cys 773 and Cys Further, since the beginning, we always found the structures of the type of inhibitors tyrphostin interesting was that it to molecules that have a degree of the electrophilic reactivity of t which may resemble. We wondered if some of this type.