Parke Davis group con independently CEP-18770 Ngig U is the same compounds. A few months after our first patent application VER Was published, the Parke Davis desire appeared. Then we filed a second patent for the other analogues. It is obvious that it amounts to Chtliche overlaps between the efforts of our two groups. The group Parke Davis was the first to public their findings in the scientific literature and in their publication to VER, With mass-spectrometric investigations, unless they more direct evidence that 6 as an irreversible inhibitor of the enzyme and identified Cys 773 as the target radical. In addition, the SAR in this series it was reported much Similar to what we observed. In particular, we found that the placement of simple substituents such as alkyl groups at the double bond to 6 acrylamide resulted in a decrease in power. Probably this was due to the reduced reactivity of t of the Michael acceptor. Zus Tzlich to the acrylamide 6, we found that the compound 7, the butynamide 6 contains an electrophilic substitution Lt is an inhibitor of EGFR kinase with an IC50 of 0.37 nm pending against the recombinant cytoplasmic Cathedral And 0 ne, 42 nM against the enzyme isolated full length L of A431 cells. This compound was our first candidate path of development, was known as the 785 and EKI has been studied extensively by our group. The compound is a potent inhibitor of EGFR autophosphorylation in intact A431 cells with an IC50 of about 5 nm, and it inhibits the proliferation of these cells in culture with an IC50 of 67 nM.
For cell line SK BR 3, a line that was overexpressed HER 2 and h NGT, inhibiition growth observed with an IC50 of 26 nm. 14C, a sample was prepared the 7 and we used showed that the compound is a covalent interaction with EGFR forms. In this experiment, the membranes of A431 cells with the labeled dose were incubated for 30 min. We observed that only a single protein consisting of the label and the expected mass was for EGFR and k Nnte with an antique Body, the EGFR are zipitiert immunpr. In addition, preincubation with the unlabeled drug blocked the incorporation of labeled drug. Third, it presents Lich in an experiment of 50 days, the compound has a profound inhibition of tumor growth in M showed Mice with the A431 xenograft model, if po dosed at 80 mg / kg on days 1 to 10 days and 21 to 30, or IP-dosed. 20 mg / kg every four days for 30 days. Discussed with the first iteration of our homology model for EGFR above, we have proposed a binding model 7 in the active site. Although this model is the b-carbon atom of cl Ture Michael acceptor at Cys 773 sulfhydryl group, we realized sp Ter, when we built the homology model improves the predicted binding mode was broken in several ways. Incidentally it is mentioned interesting to note that we and colleagues found at Case Western Reserve University found that 7 showed significant efficacy in a mouse model of polycystic kidney disease and with the staff at Johns Hopkins, we found that, in combination with anti-inflammatory stero used sulindac, 7 was in a mouse model of familial Ren sen polyposis adenomat active in humans suggests an additionally USEFUL applications for inhibitors of this type.