danusertib and Neoplasms

Topics: Animals; Antineoplastic Agents; Aurora Kinases; Drug Discovery; Humans; Mitosis; Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases

The Aurora family of serine/threonine kinases is essential for mitosis. Their crucial role in cell cycle regulation and aberrant expression in a broad range of malignancies have been demonstrated and have prompted intensive search for small molecule Aurora inhibitors. Indeed, over 10 of them have reached the clinic as potential anticancer therapies. We report herein the discovery and optimization of a novel series of tricyclic molecules that has led to SAR156497, an exquisitely selective Aurora A, B, and C inhibitor with in vitro and in vivo efficacy. We also provide insights into its mode of binding to its target proteins, which could explain its selectivity.

Topics: Animals; Antineoplastic Agents; Aurora Kinase A; Aurora Kinase B; Aurora Kinase C; Aurora Kinases; Benzimidazoles; Female; HCT116 Cells; Humans; Mice, SCID; Models, Chemical; Models, Molecular; Molecular Structure; Neoplasms; Protein Binding; Protein Kinase Inhibitors; Protein Structure, Tertiary; Quinolones; Sf9 Cells; Small Molecule Libraries; Xenograft Model Antitumor Assays