High-throughput screening campaigns against a PI3Kα isoform bearing the H1047R mutation identified potential inhibitors with novel scaffolds.

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dc.contributor.author Wang, Jia en
dc.contributor.author Gong, Grace Qun en
dc.contributor.author Zhou, Yan en
dc.contributor.author Lee, Woo Jeong en
dc.contributor.author Buchanan, Christina en
dc.contributor.author Denny, William en
dc.contributor.author Rewcastle, Gordon en
dc.contributor.author Kendall, Jackie Diane en
dc.contributor.author Dickson, James en
dc.contributor.author Flanagan, Jack en
dc.contributor.author Shepherd, Peter Robin en
dc.contributor.author Yang, De-Hua en
dc.contributor.author Wang, Ming-Wei en
dc.date.accessioned 2018-10-26T03:40:28Z en
dc.date.issued 2018-11 en
dc.identifier.issn 1671-4083 en
dc.identifier.uri http://hdl.handle.net/2292/43598 en
dc.description.abstract The phosphatidylinositol 3-kinase (PI3K) pathway is involved in many cellular functions including cell growth, metabolism, and transformation. Hyperactivation of this pathway contributes to tumorigenesis, therefore, PI3K is a major target for anticancer drug discovery. Since the PI3Kα isoform is implicated mostly in cancer, we conducted a high-throughput screening (HTS) campaign using a 3-step PI3K homogenous time-resolved fluorescence assay against this isoform bearing the H1047R mutation. A total of 288,000 synthetic and natural product-derived compounds were screened and of which, we identified 124 initial hits that were further selected by considering the predicted binding mode, relationship to known pan-assay interference compounds and previous descriptions as a lipid kinase inhibitor. A total of 24 compounds were then tested for concentration-dependent responses. These hit compounds provide novel scaffolds that can potentially be optimized to create novel PI3K inhibitors. en
dc.format.medium Print-Electronic en
dc.language eng en
dc.relation.ispartofseries Acta pharmacologica Sinica en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm en
dc.subject Humans en
dc.subject Isoenzymes en
dc.subject Protein Kinase Inhibitors en
dc.subject Protein Binding en
dc.subject Mutation en
dc.subject Hydrogen Bonding en
dc.subject High-Throughput Screening Assays en
dc.subject Phosphatidylinositol 3-Kinases en
dc.subject Molecular Docking Simulation en
dc.title High-throughput screening campaigns against a PI3Kα isoform bearing the H1047R mutation identified potential inhibitors with novel scaffolds. en
dc.type Journal Article en
dc.identifier.doi 10.1038/s41401-018-0057-z en
pubs.issue 11 en
pubs.begin-page 1816 en
pubs.volume 39 en
dc.rights.holder Copyright: The author en
pubs.end-page 1822 en
pubs.publication-status Published en
dc.rights.accessrights http://purl.org/eprint/accessRights/RestrictedAccess en
pubs.subtype research-article en
pubs.subtype Journal Article en
pubs.elements-id 747965 en
pubs.org-id Medical and Health Sciences en
pubs.org-id Medical Sciences en
pubs.org-id Auckland Cancer Research en
pubs.org-id Molecular Medicine en
pubs.org-id Pharmacology en
pubs.org-id Science en
pubs.org-id Biological Sciences en
pubs.org-id Science Research en
pubs.org-id Maurice Wilkins Centre (2010-2014) en
dc.identifier.eissn 1745-7254 en
pubs.record-created-at-source-date 2018-07-12 en
pubs.dimensions-id 29991713 en

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