8c15

Aurora A kinase in complex with TPX2-inhibitor 3

spinqualitylabelsall models 8c15, resolution 2.41Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8c15 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.41Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function AURKA_HUMAN Mitotic serine/threonine kinases that contributes to the regulation of cell cycle progression. Associates with the centrosome and the spindle microtubules during mitosis and plays a critical role in various mitotic events including the establishment of mitotic spindle, centrosome duplication, centrosome separation as well as maturation, chromosomal alignment, spindle assembly checkpoint, and cytokinesis. Required for initial activation of CDK1 at centrosomes. Phosphorylates numerous target proteins, including ARHGEF2, BORA, BRCA1, CDC25B, DLGP5, HDAC6, KIF2A, LATS2, NDEL1, PARD3, PPP1R2, PLK1, RASSF1, TACC3, p53/TP53 and TPX2. Regulates KIF2A tubulin depolymerase activity. Required for normal axon formation. Plays a role in microtubule remodeling during neurite extension. Important for microtubule formation and/or stabilization. Also acts as a key regulatory component of the p53/TP53 pathway, and particularly the checkpoint-response pathways critical for oncogenic transformation of cells, by phosphorylating and stabilizing p53/TP53. Phosphorylates its own inhibitors, the protein phosphatase type 1 (PP1) isoforms, to inhibit their activity. Necessary for proper cilia disassembly prior to mitosis. Publication Abstract from PubMed 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. Selective Aurora A-TPX2 Interaction Inhibitors Have In Vivo Efficacy as Targeted Antimitotic Agents.,Stockwell SR, Scott DE, Fischer G, Guarino E, Rooney TPC, Feng TS, Moschetti T, Srinivasan R, Alza E, Asteian A, Dagostin C, Alcaide A, Rocaboy M, Blaszczyk B, Higueruelo A, Wang X, Rossmann M, Perrior TR, Blundell TL, Spring DR, McKenzie G, Abell C, Skidmore J, Venkitaraman AR, Hyvonen M J Med Chem. 2024 Aug 27. doi: 10.1021/acs.jmedchem.4c01165. PMID:39190548 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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