ORCID Profile
0000-0003-1058-5252
Current Organisation
University of California, Irvine
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In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Macromolecular and Materials Chemistry | Synthesis of Materials | Analytical Spectrometry | Sociology and Social Studies of Science and Technology |
Organic Industrial Chemicals (excl. Resins, Rubber and Plastics) | Human Pharmaceutical Treatments (e.g. Antibiotics) | Workforce Transition and Employment
Publisher: Wiley
Date: 27-02-2017
Abstract: Selectively inhibiting target proteins in cancer cells over normal cells is one of the most critical features of a successful protein inhibitor for clinical applications. By evaluating and comparing the impact of a clinical N-terminal heat shock protein 90 (Hsp90) inhibitor, AUY922 (luminespib), on Hsp90 inhibition-associated cellular events in cancer cells versus normal cells, we found that it produces similar phenotype characteristics in both cell types, indicating that AUY922 is not selective for targeting Hsp90 in tumor cells. By comparison, the C-terminal Hsp90 modulator SM258 suppresses cell proliferation, triggers apoptosis, regulates the expression of Hsp90-associated heat shock proteins, and enhances the degradation of Hsp90's client proteins preferentially in cancer cells over normal cells. Our findings support a new paradigm that AUY922 is not tumor selective, whereas SM258 is more selective and likely acts through an Hsp90-dependent mechanism.
Publisher: American Chemical Society (ACS)
Date: 03-12-2018
DOI: 10.1021/ACS.JMEDCHEM.8B01436
Abstract: Protein-protein interactions (PPIs) regulate all signaling pathways for cellular function. Developing molecules that modulate PPIs through the interface of their protein surfaces has been a significant challenge and there has been little success controlling PPIs through standard molecular library screening approaches. PPIs control the cell's protein-folding machinery, and this machinery relies on a multiprotein complex formed with heat shock protein 70 (Hsp70). Described is the design, synthesis, and biological evaluation of molecules aimed to regulate the interaction between two proteins that are critical to the protein-folding machinery: heat shock protein 70 (Hsp70) and cochaperone heat shock organizing protein (HOP). We report the first class of compounds that directly regulate these two protein-protein interactions and inhibit protein folding events.
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D0MD00387E
Abstract: Allosteric inhibitors of Hsp90 have potential as anti-cancer agents without the side-effects that arise from targeting ATP-binding site in the N-terminal domain. This study gives NMR information on binding of allosteric inhibitor compounds to Hsp90.
Publisher: American Chemical Society (ACS)
Date: 09-03-2017
Publisher: American Chemical Society (ACS)
Date: 03-05-2021
Publisher: Wiley
Date: 20-01-2017
Abstract: The phenotypes produced when cells are treated with the heat shock protein 90 (Hsp90) inhibitors AUY922 or 17-AAG (classical inhibitors) are different to those produced when cells are knocked down with Hsp90α. Pull-down assays using classical inhibitors suggest that these molecules bind to multiple targets other than Hsp90. Classical inhibitors also induce similar protein markers as other anti-cancer therapies cisplatin and bortezomib that do not target Hsp90. Together these data suggest that AUY922 and 17-AAG acts on multiple targets and likely kills cells through multiple mechanisms. Comparing these classical inhibitors to the effects seen when treating cells with C-terminal Hsp90 modulators reveals that C-terminal modulators effectively bind to Hsp90, and induce phenotypic markers consistent with the Hsp90α CRISPR knockdown data. Our findings challenge the current interpretation of Hsp90 inhibitors and suggest that a large body of literature that describes the Hsp90 phenotype and inhibitors is re-examined in this context.
Publisher: Informa UK Limited
Date: 2019
Publisher: MDPI AG
Date: 20-03-2019
DOI: 10.3390/NANO9030465
Abstract: Semiconductor nanocrystals or quantum dots (QDs) have unique optical and physical properties that make them potential imaging tools in biological and medical applications. However, concerns over the aqueous dispersivity, toxicity to cells, and stability in biological environments may limit the use of QDs in such applications. Here, we report an investigation into the cytotoxicity of aqueously dispersed CdSe(S) and CdSe(S)/ZnO core/shell QDs in the presence of human colorectal carcinoma cells (HCT-116) and a human skin fibroblast cell line (WS1). The cytotoxicity of the precursor solutions used in the synthesis of the CdSe(S) QDs was also determined in the presence of HCT-116 cells. CdSe(S) QDs were found to have a low toxicity at concentrations up to 100 µg/mL, with a decreased cell viability at higher concentrations, indicating a highly dose-dependent response. Meanwhile, CdSe(S)/ZnO core/shell QDs exhibited lower toxicity than uncoated QDs at higher concentrations. Confocal microscopy images of HCT-116 cells after incubation with CdSe(S) and CdSe(S)/ZnO QDs showed that the cells were stable in aqueous concentrations of 100 µg of QDs per mL, with no sign of cell necrosis, confirming the cytotoxicity data.
Publisher: Elsevier BV
Date: 05-2022
DOI: 10.1016/J.BIOORG.2022.105713
Abstract: Heat shock protein 70 (Hsp70) plays a major role in protein folding and has emerged as an attractive target in a wide range of cancers. Here we used a polymer nanogel to deliver two hydrophilic peptide inhibitors that block the interaction between the C-terminus of Hsp70 and heat shock organizing protein (HOP). The nanogels are able to load ∼200 wt% of the peptide inhibitors from solution via simple agitation at pH 7, and release them after cell uptake. Delivery of Hsp70 inhibitors to HCT116 cancer cells produced a clear Hsp70 inhibition phenotype: downregulation of client proteins glucocorticoid receptor (GR), immunophilins (FKBP51 and FKBP52), the protein kinase Akt-1, as well as the co-chaperone CHIP, and they induce cancer cell death. These results showcase the advantages of using versatile nanogels for delivery of hydrophilic cargo such as peptides and demonstrate the viability of these peptide inhibitors for targeting the Hsp70-HOP interaction in a cellular system.
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C9CC00890J
Abstract: LB76 is a cyclic peptide that shows great promise as a selective heat shock protein 90 (Hsp90) inhibitor.
Publisher: Wiley
Date: 23-03-2018
DOI: 10.1002/PEP2.24063
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C8CC07576J
Abstract: Protein–protein interactions control all cellular functions. The designed cyclic peptide LB76 is shown to disrupt key PPI between Hsp90 and co-chaperones. LB76 binds selectively to Hsp90 in the cellular environment and disrupts Hsp90's protein folding activity.
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/C9PY01120J
Abstract: A pH responsive pMAA nanogel that demonstrates high loading capacity and rapid intracellular delivery of hydrophilic peptides.
Publisher: Wiley
Date: 21-01-2021
Publisher: American Chemical Society (ACS)
Date: 13-12-2018
Publisher: American Chemical Society (ACS)
Date: 24-01-2018
DOI: 10.1021/ACS.ORGLETT.7B03363
Abstract: The design, synthesis, and cell permeability of 19 hydrophilic macrocyclic peptides is presented. By systematically analyzing the impact of three different approaches (alkylated amino acids, asparagines, and d-amino acids) on the permeability of polar peptides, a well-defined strategy for optimizing cell permeability is provided. These three new methods can be used in idually or in combination to effectively convert polar peptides into cell permeable molecules, and the results can be applied to the rapidly expanding peptide therapeutic industry.
Publisher: Wiley
Date: 09-11-2020
Location: United States of America
Start Date: 07-2018
End Date: 12-2024
Amount: $3,279,502.00
Funder: Australian Research Council
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