制药公司,罗氏,Lindpainter,斯坦福大学,生物标志物-个体化用药汇总.ppt

Biomarker for ADR: DPR with 5-FU Biomarker for ADR: UGT1A1 Irinotican * * Point I’m trying to make – at the same time some of the challenge… * * * Like to strike a cautionary note… * As a curiosity, HH * * * * Figure 4. Clustering of Mutations in the EGFR Gene at Critical Sites within the ATP-Binding Pocket. Panel A shows the position of overlapping in-frame deletions in exon 19 and missense mutations in exon 21 of the EGFR gene in seven patients with non–small-cell lung cancer. The partial nucleotide sequence of each exon is shown, with deletions indicated by red dashed lines and missense mutations shown in red and underlined; the wild-type EGFR nucleotide and amino acid sequences are shown at the top. Panel B shows the tridimensional structure of the EGFR ATP cleft flanked by the N-terminal lobe and the C-terminal lobe of the kinase domain ( coordinates derived from Protein Data Bank 1M14 and displayed with the use of Cn3D software). The inhibitor (dark blue), representing gefitinib, occupies the ATP cleft. The locations of the two missense mutations are shown within the activating loop of the tyrosine kinase (light blue); the three in-frame deletions are all present within another loop (shown in red), which flanks the ATP cleft. Panel C shows a close-up view of the EGFR tyrosine kinase domain, with the critical amino acids implicated in binding to ATP or the inhibitor. Specifically, 4-anilinoquinazoline compounds such as gefitinib inhibit catalysis by occupying the ATP-binding site, where they form hydrogen bonds with methionine (M769) and cysteine 751 (C751) residues, whereas their anilino ring is close to methionine 742 (M742), lysine 721 (K721), and leucine 764 (L764)residues (all shown in green). 22 In-frame deletions within the loop that is targeted by mutations (shown in red) are predicted to alter the position of these amino acids relative to that of the inhibitor. Mutated residues (red) are shown within the activation loop of the tyrosine kinase (light