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

• Published in: Journal of medicinal chemistry Vol. 67; no. 17; pp. 15521 - 15536
• Main Authors: Stockwell, Simon R., Scott, Duncan E., Fischer, Gerhard, Guarino, Estrella, Rooney, Timothy P. C., Feng, Tzu-Shean, Moschetti, Tommaso, Srinivasan, Rajavel, Alza, Esther, Asteian, Alice, Dagostin, Claudio, Alcaide, Anna, Rocaboy, Mathieu, Blaszczyk, Beata, Higueruelo, Alicia, Wang, Xuelu, Rossmann, Maxim, Perrior, Trevor R., Blundell, Tom L., Spring, David R., McKenzie, Grahame, Abell, Chris, Skidmore, John, Venkitaraman, Ashok R., Hyvönen, Marko
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 12.09.2024; American Chemical Society
• Subjects: Animals; Antimitotic Agents - chemistry; Antimitotic Agents - pharmacology; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Aurora Kinase A - antagonists & inhibitors; Aurora Kinase A - metabolism; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Chemistry, Medicinal; Humans; Life Sciences & Biomedicine; Mice; Mice, Nude; Microtubule-Associated Proteins - metabolism; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - metabolism; Paclitaxel - pharmacology; Pharmacology & Pharmacy; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Science & Technology; Structure-Activity Relationship; Xenograft Model Antitumor Assays; A ACTIVATION; TAXANE RESISTANCE; ALISERTIB MLN8237; STRUCTURAL BASIS; PANCREATIC-CANCER; SOLID TUMORS SAFETY; CELL-CYCLE; KINASE INHIBITOR; PHASE-I; SMALL-MOLECULE INHIBITOR
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c01165

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.