Diamond Publications - Search Results

Search Again...

These results only include publications that have been reviewed and processed by Diamond Light Source. To also view papers that have not yet been processed click here.

You can use the folder icon under Actions to collate papers as required. You can then click on View Folder in the left-hand navigation to review and/or download your folder.

One item found (0 items not approved).

Instruments / Technical Area	Publication Details	Published	Actions
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I24-Microfocus Macromolecular Crystallography	Selective Aurora A-TPX2 interaction inhibitors have in vivo efficacy as targeted antimitotic agents Simon R. Stockwell , Duncan E. Scott , Gerhard Fischer , Estrella Guarino , Timothy P. C. Rooney , Tzu-Shean Feng , Tommaso Moschetti , Rajavel Srinivasan , Esther Alza , Alice Asteian , Claudio Dagostin , Anna Alcaide , Mathieu Rocaboy , Beata Blaszczyk , Alicia Higueruelo , Xuelu Wang , Maxim Rossmann , Trevor R. Perrior , Tom L. Blundell , David R. Spring , Grahame Mckenzie , Chris Abell , John Skidmore , Ashok R. Venkitaraman , Marko Hyvonen Journal Of Medicinal Chemistry 9 DOI: 10.1021/acs.jmedchem.4c01165 Diamond Proposal Number(s): [9537, 14043] Open Access Show Abstract ▼ Abstract: Aurora A kinase, a cell division regulator, is frequently overexpressed in various cancers, provoking genome instability and resistance to antimitotic chemotherapy. Localization and enzymatic activity of Aurora A are regulated by its interaction with the spindle assembly factor TPX2. We have used fragment-based, structure-guided lead discovery to develop small molecule inhibitors of the Aurora A-TPX2 protein–protein interaction (PPI). Our lead compound, CAM2602, inhibits Aurora A:TPX2 interaction, binding Aurora A with 19 nM affinity. CAM2602 exhibits oral bioavailability, causes pharmacodynamic biomarker modulation, and arrests the growth of tumor xenografts. CAM2602 acts by a novel mechanism compared to ATP-competitive inhibitors and is highly specific to Aurora A over Aurora B. Consistent with our finding that Aurora A overexpression drives taxane resistance, these inhibitors synergize with paclitaxel to suppress the outgrowth of pancreatic cancer cells. Our results provide a blueprint for targeting the Aurora A-TPX2 PPI for cancer therapy and suggest a promising clinical utility for this mode of action.	Aug 2024

Instruments / Technical Area

Publication Details

Published

Actions

I03-Macromolecular Crystallography
I04-1-Macromolecular Crystallography (fixed wavelength)
I24-Microfocus Macromolecular Crystallography

Selective Aurora A-TPX2 interaction inhibitors have in vivo efficacy as targeted antimitotic agents