of AKT several hours to inhibit the proliferation of cancer cells, the information was very useful in lead optimization and identification GDC 0941 as clinical candidates and also teaches clinical studies. Moreover, this group of compounds inhibited the translocation of the transcription factor forkhead FKHR with EC50 values of 30 81nM in accordance with the inhibition of PI3K. Showed in vivo animal model that the significant reduction in glucuronidation GDC 0941 by the substitution offered indazole Born systemic clearance significantly slower compared to IP 103, IP 540 and KW-2478 IP 640 registered and also performs oral bioavailability is 78 M Usen a significant advantage over other analogues. This has led to deep and long inhibition of PI3-kinase biomarkers in xenografts of human cancer, in accordance with zinc Gerter tumor exposure to the drug. Thus levels of tumors were significantly concentrations for at least 6 hours on antiproliferative GI50 and reduced phosphorylation of AKT was kept GSK3 and p70S6K for at least 8 hours. Because of these improved pharmacokinetic and pharmacodynamic properties, GDC 0941 excellent dose of therapeutic activity T in PTEN function showed 0 pathwayaddicted PI3K U87MG human glioblastoma xenograft model in Nacktm Nozzles observed with up to 98 significant growth inhibition and regression in this model.
Efficacy was in the PI3K CONFIRMS addicted IGROV a xenograft model of human ovarian cancer, which has a deletion and best hetT319F reading frame PTEN mutation and a p85 binding domain Ne of p110 has hetR38C. The therapeutic activity of t Detected in other human tumor NVP-AUY922 xenografts. The association between exposure to pharmacokinetics, pharmacodynamics provided Changes biomarker PI3K Pathway and drug response convincing pharmacological audit trail, which is a good basis for further clinical studies. Attractive based on its molecular profile, pharmacological and therapeutic, including minimal effects on cytochrome P450 and hERG, GDC 0941 for the clinical development was Selected Hlt. Structural studies of the PI3 kinome: from valuable information and excellent design issues of the GDC 0941 was gem of structural data on PI3Ks and their interactions with small-molecule inhibitors, a situation that is almost taken issued out many current programs aimed l on drug discovery soluble drugs. However, it was only a decade ago that the first light on the three-dimensional structure of PI3Ks with Aufkl Tion of apo-bound and ATP crystal structures of pig p110 ? was shed. These studies have a cathedral Nenstruktur of five years, which is an N-terminal adapter connection, a Ras Bindungsdom ne, A C2 Dom ne, which has been suggested to be involved in membrane binding elements, a FELDH Ckslers includes revealed Dal and a catalytic Cathedral ne. The fold of the catalytic Cathedral Ruixing lipid kinase proved to be very Similar both protein kinase archetype, and includes