mk-8745 and Neoplasms

The Aurora family of serine/threonine kinases in mammals are key regulators of mitotic progression and are commonly upregulated in human tumors. Since AURKA's increased expression has been linked to cancer, AURKA inhibitors could reduce AURKA expression and function as potent therapeutic drugs. The study's objective was to find and categorize inhibitors with a stronger affinity for AURKA. This study also aimed to identify AURKA's expression profile and prognostic significance across pan-cancers. We looked into therapeutic compounds that were structurally comparable to MK8745 for their potential to selectively inhibit AURKA. We used drug likeliness analysis, MD simulation studies to evaluate the therapeutic possibility of screened MK8745 analogues. AURKA was found to be strongly upregulated in several cancers and is linked to worse overall and relapse-free survival. The Molecular docking and dynamic analysis revealed two new MK8745 analogues to be potent AURKA inhibitors with higher binding affinities and stabilities than MK8745. Furthermore, MK8745 analogues are potential replacements for MK8745 because they have strong binding affinity, which is consistent with MDS results, and have appropriate ADMET properties. Through basic, clinical, and preclinical research, the identification of novel compounds may open the door for their prospective use in the prevention of cancer.

Topics: Animals; Aurora Kinase A; Cell Line, Tumor; Humans; Mammals; Molecular Docking Simulation; Neoplasms; Piperazines; Serine; Thiazoles; Threonine

We have previously shown that mammary tumorigenesis in MMTV-Aurora-A mice is further enhanced when p53 is inactivated, demonstrating that integrity of p53 pathway determines phenotypes induced by this oncogenic kinase. In this study, we investigated the roles of genes involved in p53 pathway (p53, Puma, p21, Bax, and Chk2) in response to Aurora-A inhibitors, VX680 and MK-8745, and explored whether chemoresistant tumor cells would further undergo apoptosis with other therapeutic agents. Isogenic HCT116 cell lines were treated with VX680 or MK-8745. Cell cycle analysis, apoptosis, and tumorigenesity were studied. Chemoresistant cells were recovered from xenograft, and further induction of apoptosis was studied. Induction of apoptosis and aneuploidy with VX680 is much stronger than MK-8745. Xenograft assay indicates that tumor growth of HCT116 and HCT116 p53(-) cells are strongly inhibited by VX680, while that of other cell types are similarly inhibited by two compounds. Among the established cell lines recovered from xenografts, MK-8745-resistant clones contain elevated phosphorylation of mTOR and Akt. When further treated with inhibitors of both mTOR and Akt, those cells undergo apoptosis. These results indicate that p53-associated pathway plays a crucial role in regulating growth inhibition of tumor cells when treated with Aurora-A inhibitors. Combined treatment with Akt/mTOR inhibitors can further induce apoptosis of Aurora-A tumors.

Topics: Animals; Apoptosis; Aurora Kinase A; Aurora Kinases; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Drug Resistance, Neoplasm; Female; HCT116 Cells; Humans; Mice; Neoplasms; Phosphorylation; Piperazines; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Thiazoles; TOR Serine-Threonine Kinases; Tumor Burden; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays