observed in sidechain conformations of Asp933, Asp805, Leu807 and Ly802 important for inhibitor binding. AZD6482 Pinson et al. Page 20 ChemMedChem. Author manuscript; available in PMC 2011 October 5. HHMI Author Manuscript HHMI Author Manuscript HHMI Author Manuscript Figure 9. Alignment of 2rd0 and model 5 highlighting differences observed in sidechain Asp805, Leu807 and Lys802 conformations important for inhibitor binding. Pinson et al. Page 21 ChemMedChem. Author manuscript; available in PMC 2011 October 5. HHMI Author Manuscript HHMI Author Manuscript HHMI Author Manuscript HHMI Author Manuscript HHMI Author Manuscript HHMI Author Manuscript Pinson et al. Page 22 Table 1 IC50 values of selected compounds v. PI3Kα and PI3Kγ.Cpd # IC50/ v. PI3KαIC50/ v. PI3Kγ IC-50 Ratio α:γ1 4.5 0.30 18 2 0.060 0.
0080 7.5 3 0.050 0.040 1.3 4 0.25 0.10 2.5 5 0.45 0.12 3.8 6 50 100 0.50 7 1.9 1.0 1.9 8 7.3 27 0.30 9 4.4 9.3 0.50 10 2.7 4.9 0.60 11 0.069 0.042 1.6 12 0.15 0.12 1.2 13 2.7 0.25 11 14 11 1.5 7.1 15 9.4 Panobinostat 3.1 3.1 16 86 4.0 22 17 22 1.4 16 19 0.0030 0.0013 2.2 20 8.3 0.62 13 40 3.0 0.41 7.3 41 11 1.4 7.9 42 0.14 0.060 2.3 43 8.7 100 0.087 44 9.0 100 0.090 45 0.40 0.20 2.0 46.10.025 4.0 47 0.80 1.0 0.80 ChemMedChem. Author manuscript; available in PMC 2011 October 5. HHMI Author Manuscript HHMI Author Manuscript HHMI Author Manuscript Pinson et al. Page 23 Table 2 Summary table of G-Score, ROC and Enrichment at 20% for protonated TZD ligands. Structure Av., median G-Score G-Score range ROC Enrichment 2a5u ?.59, ?.69 ?0.14, ?.75 0.849 65.4% 2wxl ?.85, ?.96 ?1.73, ?.57 0.912 76.9% 2rd0 ?.
39, ?.46 ?.31, ?.96 0.748 23.1% +Induced Fit ?.15, ?.14 ?.57, ?.82 0.772 32.7%α-model ?.46, ?.61 ?3.69, ?.13 0.721 34.6% +Induced Fit ?.82, ?.03 ?2.41, ?.84 0.788 61.5% ?.54, ?.62 ?2.41, ?.84 0.900 65.4% ChemMedChem. Author manuscript; available in PMC 2011 October 5. Cancer-derived mutations in the regulatory subunit p85α of phosphoinositide 3-kinase function through the catalytic subunit p110αMinghao Sun1, Petra Hillmann1, Bianca T. Hofmann2, Jonathan R. Hart, and Peter K. Vogt3 Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037 Contributed by Peter K. Vogt, July 6, 2010 Cancer-specific mutations in the iSH2 and nSH2 domains of p85α, the regulatory subunit of phosphatidylinositide 3-kinase , show gain of function.
They induce oncogenic cellular transformation, stimulate cellular proliferation, and enhance PI3K signaling. Quantitative determinations of oncogenic activity reveal large differences between individual mutants of p85α. The mutant proteins are still able to bind to the catalytic subunits p110α and p110β. Studies with isoform-specific inhibitors of p110 suggest that expression of p85 mutants in fibroblasts leads exclusively to an activation of p110α, and p110α is the sole mediator of p85 mutant-induced oncogenic transformation. The characteristics of the p85 mutants are in agreement with the hypothesis that the mutations weaken an inhibitory interaction between p85αand p110α while preserving the stabilizing interaction between p85α iSH2 and the adapter-binding domain of p110α.
oncogenic transformation | target of rapamycin The phosphoinositide 3-kinase signaling pathway is deregulated in most human cancers by differential gene expression, amplification, or mutation. Of particular interest are mutations that occur in the catalytic subunit p110α of class I PI3K, because they confer a strong gain of function upon the enzyme, resulting in enhanced catalytic activity, constitutive signaling, and oncogenicity in vitro and in vivo. There have also been