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Your search keyword '"McKenzie, Grahame"' showing total 5 results
Start Over Author "McKenzie, Grahame" Topic aurora kinase a
5 results on '"McKenzie, Grahame"'

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

Author

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, and Hyvönen M

Subjects
Humans, Animals, Cell Line, Tumor, Mice, Nuclear Proteins metabolism, Nuclear Proteins antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors chemistry, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Structure-Activity Relationship, Paclitaxel pharmacology, Mice, Nude, Aurora Kinase A antagonists & inhibitors, Aurora Kinase A metabolism, Cell Cycle Proteins antagonists & inhibitors, Cell Cycle Proteins metabolism, Antimitotic Agents pharmacology, Antimitotic Agents chemistry, Microtubule-Associated Proteins metabolism
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.

Published
2024
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2. Computationally-guided optimization of small-molecule inhibitors of the Aurora A kinase-TPX2 protein-protein interaction.

Author

Cole DJ, Janecek M, Stokes JE, Rossmann M, Faver JC, McKenzie GJ, Venkitaraman AR, Hyvönen M, Spring DR, Huggins DJ, and Jorgensen WL

Subjects
Aurora Kinase A chemistry, Aurora Kinase A metabolism, Cell Cycle Proteins chemistry, Cell Cycle Proteins metabolism, Humans, Microtubule-Associated Proteins chemistry, Microtubule-Associated Proteins metabolism, Models, Molecular, Molecular Structure, Nuclear Proteins chemistry, Nuclear Proteins metabolism, Protein Binding drug effects, Protein Kinase Inhibitors chemistry, Small Molecule Libraries chemistry, Aurora Kinase A antagonists & inhibitors, Cell Cycle Proteins antagonists & inhibitors, Microtubule-Associated Proteins antagonists & inhibitors, Molecular Dynamics Simulation, Nuclear Proteins antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Small Molecule Libraries pharmacology
Abstract

Free energy perturbation theory, in combination with enhanced sampling of protein-ligand binding modes, is evaluated in the context of fragment-based drug design, and used to design two new small-molecule inhibitors of the Aurora A kinase-TPX2 protein-protein interaction.

Published
2017
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3. Allosteric modulation of AURKA kinase activity by a small-molecule inhibitor of its protein-protein interaction with TPX2.

Author

Janeček M, Rossmann M, Sharma P, Emery A, Huggins DJ, Stockwell SR, Stokes JE, Tan YS, Almeida EG, Hardwick B, Narvaez AJ, Hyvönen M, Spring DR, McKenzie GJ, and Venkitaraman AR

Subjects
Cell Line, Tumor, HeLa Cells, Humans, Mitosis drug effects, Neoplasm Proteins metabolism, Phosphoproteins metabolism, Protein Binding drug effects, Spindle Apparatus drug effects, Aurora Kinase A metabolism, Cell Cycle Proteins metabolism, Microtubule-Associated Proteins metabolism, Nuclear Proteins metabolism, Protein Interaction Maps drug effects, Protein Kinases metabolism, Small Molecule Libraries pharmacology
Abstract

The essential mitotic kinase Aurora A (AURKA) is controlled during cell cycle progression via two distinct mechanisms. Following activation loop autophosphorylation early in mitosis when it localizes to centrosomes, AURKA is allosterically activated on the mitotic spindle via binding to the microtubule-associated protein, TPX2. Here, we report the discovery of AurkinA, a novel chemical inhibitor of the AURKA-TPX2 interaction, which acts via an unexpected structural mechanism to inhibit AURKA activity and mitotic localization. In crystal structures, AurkinA binds to a hydrophobic pocket (the 'Y pocket') that normally accommodates a conserved Tyr-Ser-Tyr motif from TPX2, blocking the AURKA-TPX2 interaction. AurkinA binding to the Y- pocket induces structural changes in AURKA that inhibit catalytic activity in vitro and in cells, without affecting ATP binding to the active site, defining a novel mechanism of allosteric inhibition. Consistent with this mechanism, cells exposed to AurkinA mislocalise AURKA from mitotic spindle microtubules. Thus, our findings provide fresh insight into the catalytic mechanism of AURKA, and identify a key structural feature as the target for a new class of dual-mode AURKA inhibitors, with implications for the chemical biology and selective therapeutic targeting of structurally related kinases.

Published
2016
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4. Computationally-guided optimization of small-molecule inhibitors of the Aurora A kinase-TPX2 protein-protein interaction

Author

Cole, Daniel J, Janecek, Matej, Stokes, Jamie E, Rossmann, Maxim, Faver, John C, McKenzie, Grahame J, Venkitaraman, Ashok R, Hyvönen, Marko, Spring, David R, Huggins, David J, Jorgensen, William L, Cole, Daniel J [0000-0003-2933-0719], Janecek, Matej [0000-0003-0740-641X], Rossmann, Maxim [0000-0001-8811-3277], Venkitaraman, Ashok R [0000-0002-6876-2672], Hyvönen, Marko [0000-0001-8683-4070], Spring, David R [0000-0001-7355-2824], Huggins, David J [0000-0003-1579-2496], Jorgensen, William L [0000-0002-3993-9520], and Apollo - University of Cambridge Repository

Subjects
Models, Molecular, Small Molecule Libraries, Molecular Structure, Humans, Nuclear Proteins, Cell Cycle Proteins, Molecular Dynamics Simulation, Microtubule-Associated Proteins, Protein Kinase Inhibitors, Aurora Kinase A, Protein Binding
Abstract

Free energy perturbation theory, in combination with enhanced sampling of protein-ligand binding modes, is evaluated in the context of fragment-based drug design, and used to design two new small-molecule inhibitors of the Aurora A kinase-TPX2 protein-protein interaction.

Published
2017

5. Allosteric modulation of AURKA kinase activity by a small-molecule inhibitor of its protein-protein interaction with TPX2

Author

Janeček, Matej, Rossmann, Maxim, Sharma, Pooja, Emery, Amy, Huggins, David J, Stockwell, Simon R, Stokes, Jamie E, Tan, Yaw S, Almeida, Estrella Guarino, Hardwick, Bryn, Narvaez, Ana J, Hyvönen, Marko, Spring, David R, McKenzie, Grahame J, Venkitaraman, Ashok R, Rossmann, Maxim [0000-0001-8811-3277], Huggins, David [0000-0003-1579-2496], Stockwell, Simon [0000-0002-3345-8945], Spring, David [0000-0001-7355-2824], and Apollo - University of Cambridge Repository

Subjects
Mitosis, Nuclear Proteins, Cell Cycle Proteins, Spindle Apparatus, Phosphoproteins, Neoplasm Proteins, Small Molecule Libraries, Cell Line, Tumor, Humans, Protein Interaction Maps, Microtubule-Associated Proteins, Protein Kinases, Aurora Kinase A, HeLa Cells, Protein Binding
Abstract

The essential mitotic kinase Aurora A (AURKA) is controlled during cell cycle progression via two distinct mechanisms. Following activation loop autophosphorylation early in mitosis when it localizes to centrosomes, AURKA is allosterically activated on the mitotic spindle via binding to the microtubule-associated protein, TPX2. Here, we report the discovery of AurkinA, a novel chemical inhibitor of the AURKA-TPX2 interaction, which acts via an unexpected structural mechanism to inhibit AURKA activity and mitotic localization. In crystal structures, AurkinA binds to a hydrophobic pocket (the 'Y pocket') that normally accommodates a conserved Tyr-Ser-Tyr motif from TPX2, blocking the AURKA-TPX2 interaction. AurkinA binding to the Y- pocket induces structural changes in AURKA that inhibit catalytic activity in vitro and in cells, without affecting ATP binding to the active site, defining a novel mechanism of allosteric inhibition. Consistent with this mechanism, cells exposed to AurkinA mislocalise AURKA from mitotic spindle microtubules. Thus, our findings provide fresh insight into the catalytic mechanism of AURKA, and identify a key structural feature as the target for a new class of dual-mode AURKA inhibitors, with implications for the chemical biology and selective therapeutic targeting of structurally related kinases.

Published
2016

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