MPC-3100 HSP90 Inhibitors come to our second clinical candidate first Our model

E by the position of the anilino four times in MPC-3100 HSP90 Inhibitors succession an improved inhibitory activity of t in the kinase assay HER 2 We initiated a study to examine in more detail, where we see the L Length of the para-position anilino substituent 4 is varied. This effort has come to our second clinical candidate first Our model for the binding of this inhibitor of the catalytic site of HER 2 in Figure 6 The connection is proposed to form the same types of interactions with the protein, as discussed above for our model EGFR. The compound inhibited both HER-2 and EGFR autophosphorylation enzyme at concentrations comparable with IC50 values of 59 and 92 nm, and was as effective in inhibiting the autophosphorylation of the receptor and growth of both EGFR and HER 2-dependent Ngigen cell lines. In the cells at low concentrations, inhibits the phosphorylation of a protein according to the receiver singer in the signal path. In addition, inhibition of receptor autophosphorylation was observed in vivo. The compound also showed a high Ma selectivity of t for members of the ErbB family JAK-STAT Signaling of kinases, when tested on a panel of different kinases. As before, we have radiolabeled drug, the best term to irreversible binding. The compound is a very effective inhibitor of tumor growth in a variety of models Xenograph after oral administration. Our pharmacokinetic and toxicology studies were without significant adverse effects, which conducted an IND submission in June 2003. As discussed above, the unique structure of the kinase inhibitor as the electrophile targeting the chemical reactivity t of a cysteine residue in the ATP active site is occupied. This residue is most distinguished by its location from other cysteine residues, despite the high sequence homology of the kinase-active sites. A cysteine residue at the position of Cys 773 in EGFR is rare in other protein kinases, but conserved in three of the four ErbB family members.
This feature combined with the chemical structure cyanoquinolin, but not enough to gain an advantage selectivity t has shown for HKI 272 within the ErbB family inhibitor for the corresponding 4-6 was anilinoquinazoline. As a result of this, HKI pan 272 as an inhibitor of the members of this family of receptor kinases important factor to be considered. Somatic mutations of EGFR and their relevance for irreversible inhibitors W During clinical studies with EKB 569 and 272 were HKI go, clinical experience with gefitinib and erlotinib reversible inhibitors highlighted Important information about some of the somatic mutations in the EGFR kinase Cathedral Bay 43-9006 sharing plans. These mutations k Can in two categories, those that activating mutations leading to a increased Hten sensitivity of tumors to inhibition by drugs against EGFR and those that are entered from tumors treated with these drugs purchased Ing resistance to these drugs. Several large studies have recently appeared, where EKB 569 and 272 to the HKI reversible inhibitors gefitinib and erlotinib were compared. These critics also have antitumor activity t of irreversible inhibitors in patients with NSCLC and therapeutic potential to treat resistant to gefitinib and erlotinib emphasized to overcome.