Docking Studies on Isoform-Specific Inhibition of Phosphoinositide-3-Kinases

Phosphatidylinositol 3-kinase α (PI3Kα) is a promising target for anticancer drug design. Oncogenic mutation H1047R in the catalytic domain is observed in many tumors and may enhance PI3Kα kinase activity by affecting loop confirmations as well as membrane binding. We applied docking methods to 33 PI3K inhibitors against the wild type (wt) PI3Kα, the H1047R mutant of PI3Kα and the γ isoform of PI3K (PI3Kγ). We also investigated the effect of protein flexibility on ligand binding by docking the same set of ligands to conformations of the wt and mutant PI3Kα generated by molecular dynamics simulations. Our data suggests that conformational differences in Gln859, Ser854, Tyr836, and Ser774 between the PI3Kα wt and H1047R mutant may be used to design ligands that are active against both the wt and H1047R mutant isoforms. Gln859, Ser854 and Ser774 may play critical roles in ligand binding to the α isoform H1047R mutant while formation of H-bonds with Ser806 of PI3Kγ may enhance γ-isoform-specific inhibition. In addition to H-bond interactions, structural and size differences in the activation and hydrophobic domains of PI3Kα, PI3Kγ, and the PI3Kα H1047R mutant could be exploited to direct the design of isoform- and/or mutant-specific PI3K inhibitors. Our data provide a reasonable explanation for the activity and selectivity of small molecular PI3K inhibitors and are in good agreement with available experimental and computational data.

[1]  M. Lambert,et al.  A novel dimer configuration revealed by the crystal structure at 2.4 Å resolution of human interleukin-5 , 1993, Nature.

[2]  Li Zhao,et al.  Oncogenic PI3K deregulates transcription and translation , 2005, Nature Reviews Cancer.

[3]  L. Toral-Barza,et al.  Synthesis and structure-activity relationships of ring-opened 17-hydroxywortmannins: potent phosphoinositide 3-kinase inhibitors with improved properties and anticancer efficacy. , 2008, Journal of medicinal chemistry.

[4]  R. Copeland,et al.  Effects of oncogenic p 110 α subunit mutations on the lipid kinase activity of phosphoinositide 3-kinase , 2007 .

[5]  Kaushik Raha,et al.  Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin. , 2010, ACS medicinal chemistry letters.

[6]  Sophie Gale,et al.  28th Annual JPMorgan Healthcare Conference--Exelixis and Nektar Therapeutics. , 2010, IDrugs : the investigational drugs journal.

[7]  H. Carlson,et al.  Computational studies and peptidomimetic design for the human p53–MDM2 complex , 2004, Proteins.

[8]  Q. She,et al.  Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restoration of PTEN function or pharmacologic modulation of constitutive phosphatidylinositol 3'-kinase/Akt pathway signaling. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[9]  S. Andreola,et al.  PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. , 2009, Annals of oncology : official journal of the European Society for Medical Oncology.

[10]  M. Zvelebil,et al.  Structural analysis of PI3-kinase isoforms: identification of residues enabling selective inhibition by small molecule ATP-competitive inhibitors. , 2008, Archives of biochemistry and biophysics.

[11]  Yigong Shi,et al.  Structural analysis of a functional DIAP1 fragment bound to grim and hid peptides. , 2001, Molecular cell.

[12]  Daniela Gabriel,et al.  Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity , 2008, Molecular Cancer Therapeutics.

[13]  R. Abraham,et al.  ATP-competitive inhibitors of the mammalian target of rapamycin: design and synthesis of highly potent and selective pyrazolopyrimidines. , 2009, Journal of medicinal chemistry.

[14]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. , 2001, Advanced drug delivery reviews.

[15]  M. Waterfield,et al.  Synthesis and biological evaluation of pyrido[3′,2′:4,5]furo[3,2- d ]pyrimidine derivatives as novel PI3 kinase p110α inhibitors , 2007 .

[16]  H M Holden,et al.  Carbamoyl phosphate synthetase: caught in the act of glutamine hydrolysis. , 1998, Biochemistry.

[17]  V. Hornak,et al.  Comparison of multiple Amber force fields and development of improved protein backbone parameters , 2006, Proteins.

[18]  J. Dodge,et al.  Studies on the mechanism of phosphatidylinositol 3-kinase inhibition by wortmannin and related analogs. , 1996, Journal of medicinal chemistry.

[19]  Liisa Holm,et al.  DaliLite workbench for protein structure comparison , 2000, Bioinform..

[20]  M. Waterfield,et al.  Synthesis and biological evaluation of 4-morpholino-2-phenylquinazolines and related derivatives as novel PI3 kinase p110alpha inhibitors. , 2006, Bioorganic & medicinal chemistry.

[21]  NMR structure of the hypothetical protein encoded by the YjbJ gene from Escherichia coli , 2002, Proteins.

[22]  J. Ptak,et al.  High Frequency of Mutations of the PIK3CA Gene in Human Cancers , 2004, Science.

[23]  K. Okkenhaug,et al.  Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. , 2001, Annual review of cell and developmental biology.

[24]  Ya-wen Wang,et al.  Pharmacophore modeling and 3D-QSAR analysis of phosphoinositide 3-kinase p110α inhibitors , 2010, Journal of molecular modeling.

[25]  L. Mario Amzel,et al.  The Structure of a Human p 110 a / p 85 a Complex Elucidates the Effects of Oncogenic PI 3 K a Mutations , 2007 .

[26]  Ming Han,et al.  Class I Phospho-inositide-3-kinases (PI3Ks) Isoform-Specific Inhibition Study by the Combination of Docking and Molecular Dynamics Simulation , 2010, J. Chem. Inf. Model..

[27]  T. Darden,et al.  Particle mesh Ewald: An N⋅log(N) method for Ewald sums in large systems , 1993 .

[28]  Pixu Liu,et al.  Targeting the phosphoinositide 3-kinase pathway in cancer , 2009, Nature Reviews Drug Discovery.

[29]  M SoestvanR.W.,et al.  Liphagal, a Selective Inhibitor of PI3 Kinase ά Isolated from the Sponge Aka coralliphaga: Structure Elucidation and Biomimetic Synthesis , 2006 .

[30]  M. Waterfield,et al.  Signaling by distinct classes of phosphoinositide 3-kinases. , 1999, Experimental cell research.

[31]  L. Cantley,et al.  Transformation of chicken cells by the gene encoding the catalytic subunit of PI 3-kinase. , 1997, Science.

[32]  K. Kinzler,et al.  A frequent kinase domain mutation that changes the interaction between PI3Kα and the membrane , 2009, Proceedings of the National Academy of Sciences.

[33]  Roger L. Williams,et al.  Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. , 2000, Molecular cell.

[34]  W. Denny,et al.  Synthesis, biological evaluation and molecular modelling of sulfonohydrazides as selective PI3K p110α inhibitors , 2007 .

[35]  W. L. Jorgensen,et al.  Comparison of simple potential functions for simulating liquid water , 1983 .