8C14

Aurora A kinase in complex with TPX2-inhibitor 9

PDB DOI: https://doi.org/10.2210/pdb8C14/pdb

Classification: CELL CYCLE
Organism(s): Homo sapiens
Expression System: Escherichia coli BL21(DE3)
Mutation(s): No

Deposited: 2022-12-20 Released: 2024-01-10
Deposition Author(s): Fischer, G., Rocaboy, M., Blaszczyk, B., Moschetti, T., Wang, X., Scott, D.E., Coyne, A.G., Dagostin, C., Rooney, T., Bayly, A., Feng, J., Asteian, A., Alcaide-Lopez, A., Stockwell, S., Skidmore, J., Venkitaraman, A.R., Abell, C., Blundell, T.L., Hyvonen, M.
Funding Organization(s): Wellcome Trust

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.93 Å
R-Value Free: 0.194
R-Value Work: 0.181
R-Value Observed: 0.182

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Literature

Selective Aurora A-TPX2 Interaction Inhibitors Have In Vivo Efficacy as Targeted Antimitotic Agents.

Stockwell, S.R., Scott, D.E., Fischer, G., Guarino, E., Rooney, T.P.C., Feng, T.S., Moschetti, T., Srinivasan, R., Alza, E., Asteian, A., Dagostin, C., Alcaide, A., Rocaboy, M., Blaszczyk, B., Higueruelo, A., Wang, X., Rossmann, M., Perrior, T.R., Blundell, T.L., Spring, D.R., McKenzie, G., Abell, C., Skidmore, J., Venkitaraman, A.R., Hyvonen, M.

(2024) J Med Chem 67: 15521-15536

PubMed: 39190548 Search on PubMed
DOI: https://doi.org/10.1021/acs.jmedchem.4c01165
Primary Citation of Related Structures:
8C14, 8C15, 8C1D, 8C1E, 8C1F, 8C1G, 8C1H, 8C1I, 8C1K, 8C1M

PubMed 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.

Organizational Affiliation

Medical Research Council Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, U.K.

Macromolecule Content

Total Structure Weight: 33.71 kDa
Atom Count: 2,513
Modelled Residue Count: 264
Deposited Residue Count: 272
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Aurora kinase A	A	272	Homo sapiens	Mutation(s): 0 Gene Names: AURKA, AIK, AIRK1, ARK1, AURA, AYK1, BTAK, IAK1, STK15, STK6 EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for O14965 (Homo sapiens) Explore O14965 Go to UniProtKB: O14965
PHAROS: O14965 GTEx: ENSG00000087586
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	O14965
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 9 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
ADP Query on ADP Download Ideal Coordinates CCD File SDF format, chain R [auth A] MOL2 format, chain R [auth A] mmCIF format, chain R [auth A]	R [auth A]	ADENOSINE-5'-DIPHOSPHATE C₁₀ H₁₅ N₅ O₁₀ P₂ XTWYTFMLZFPYCI-KQYNXXCUSA-N		Interactions Focus chain R [auth A] Interactions & Density Focus chain R [auth A]
T0L (Subject of Investigation/LOI) Query on T0L Download Ideal Coordinates CCD File SDF format, chain Y [auth A] MOL2 format, chain Y [auth A] mmCIF format, chain Y [auth A]	Y [auth A]	4-(4-chloranyl-3-cyano-phenyl)-1~{H}-indole-6-carboxylic acid C₁₆ H₉ Cl N₂ O₂ LOEVXPKFXLHBHC-UHFFFAOYSA-N		Interactions Focus chain Y [auth A] Interactions & Density Focus chain Y [auth A]
T5L Query on T5L Download Ideal Coordinates CCD File SDF format, chain S [auth A] MOL2 format, chain S [auth A] mmCIF format, chain S [auth A]	S [auth A]	(1~{R},2~{R})-cyclohexane-1,2-dicarboxylic acid C₈ H₁₂ O₄ QSAWQNUELGIYBC-PHDIDXHHSA-N		Interactions Focus chain S [auth A] Interactions & Density Focus chain S [auth A]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain E [auth A] MOL2 format, chain E [auth A] mmCIF format, chain E [auth A]	E [auth A]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain E [auth A] Interactions & Density Focus chain E [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain T [auth A] SDF format, chain U [auth A] SDF format, chain V [auth A] SDF format, chain W [auth A] SDF format, chain X [auth A] MOL2 format, chain T [auth A] MOL2 format, chain U [auth A] MOL2 format, chain V [auth A] MOL2 format, chain W [auth A] MOL2 format, chain X [auth A] mmCIF format, chain T [auth A] mmCIF format, chain U [auth A] mmCIF format, chain V [auth A] mmCIF format, chain W [auth A] mmCIF format, chain X [auth A]	T [auth A], U [auth A], V [auth A], W [auth A], X [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain T [auth A] Focus chain U [auth A] Focus chain V [auth A] Focus chain W [auth A] Focus chain X [auth A] Interactions & Density Focus chain T [auth A] Focus chain U [auth A] Focus chain V [auth A] Focus chain W [auth A] Focus chain X [auth A]
DMS Query on DMS Download Ideal Coordinates CCD File SDF format, chain L [auth A] SDF format, chain M [auth A] SDF format, chain N [auth A] SDF format, chain O [auth A] MOL2 format, chain L [auth A] MOL2 format, chain M [auth A] MOL2 format, chain N [auth A] MOL2 format, chain O [auth A] mmCIF format, chain L [auth A] mmCIF format, chain M [auth A] mmCIF format, chain N [auth A] mmCIF format, chain O [auth A]	L [auth A], M [auth A], N [auth A], O [auth A]	DIMETHYL SULFOXIDE C₂ H₆ O S IAZDPXIOMUYVGZ-UHFFFAOYSA-N		Interactions Focus chain L [auth A] Focus chain M [auth A] Focus chain N [auth A] Focus chain O [auth A] Interactions & Density Focus chain L [auth A] Focus chain M [auth A] Focus chain N [auth A] Focus chain O [auth A]
ACT Query on ACT Download Ideal Coordinates CCD File SDF format, chain P [auth A] SDF format, chain Q [auth A] MOL2 format, chain P [auth A] MOL2 format, chain Q [auth A] mmCIF format, chain P [auth A] mmCIF format, chain Q [auth A]	P [auth A], Q [auth A]	ACETATE ION C₂ H₃ O₂ QTBSBXVTEAMEQO-UHFFFAOYSA-M		Interactions Focus chain P [auth A] Focus chain Q [auth A] Interactions & Density Focus chain P [auth A] Focus chain Q [auth A]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain J [auth A] SDF format, chain K [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain K [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain K [auth A]	F [auth A] G [auth A] H [auth A] I [auth A] J [auth A] F [auth A], G [auth A], H [auth A], I [auth A], J [auth A], K [auth A]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Interactions & Density Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain B [auth A] SDF format, chain C [auth A] SDF format, chain D [auth A] MOL2 format, chain B [auth A] MOL2 format, chain C [auth A] MOL2 format, chain D [auth A] mmCIF format, chain B [auth A] mmCIF format, chain C [auth A] mmCIF format, chain D [auth A]	B [auth A], C [auth A], D [auth A]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain B [auth A] Focus chain C [auth A] Focus chain D [auth A] Interactions & Density Focus chain B [auth A] Focus chain C [auth A] Focus chain D [auth A]