Aurora A Kinase inhibitors in prostate cancer

Epithelial ovarian cancer (EOC) is deadliest gynecological malignancy with poor prognosis and patient survival. Despite development of several therapeutic interventions such as poly-ADP ribose polymerase (PARP) inhibitors, EOC remains unmanageable and discovery of novel early detection biomarkers and treatment targets are highly warranted. Although neuroendocrine differentiation (NED) is implicated in different human cancers including prostate adenocarcinoma and lung cancer, mechanistic studies concerning NED of epithelial ovarian cancer are lacking...

Aurora-A (AURKA) is serine/threonine protein kinase involved in the regulation of numerous processes of cell division. Numerous studies have demonstrated strong association between AURKA and cancer. AURKA is overexpressed in many cancers, such as colon, breast and prostate cancers. Consequently, AURKA has emerged as promising target for therapeutic intervention in cancer management. Herein, we describe a computational workflow for the discovery of novel anti-AURKA inhibitory leads starting with ligand-based assessment of the pharmacophoric space of six diverse sets of inhibitors...

The (poly)pharmacology of drug metabolites is seldom comprehensively characterized in drug discovery. However, some drug metabolites can reach high plasma concentrations and display in vivo activity. Here, we use computational and experimental methods to comprehensively characterize the kinase polypharmacology of M324, the major metabolite of the PARP1 inhibitor rucaparib. We demonstrate that M324 displays unique PLK2 inhibition at clinical concentrations. This kinase activity could have implications for the efficacy and safety of rucaparib and therefore warrants further clinical investigation...

PURPOSE: This first-in-human phase I dose-escalation study evaluated the safety, pharmacokinetics, and efficacy of tinengotinib (TT-00420), a multi-kinase inhibitor targeting fibroblast growth factor receptors 1-3 (FGFRs 1-3), Janus kinase 1/2, vascular endothelial growth factor receptors, and Aurora A/B, in patients with advanced solid tumors. PATIENTS AND METHODS: Patients received tinengotinib orally daily in 28-day cycles. Dose escalation was guided by Bayesian modeling using escalation with overdose control...

CXCR7 is an atypical chemokine receptor that recruits β-arrestin (ARRB2) and internalizes into clathrin-coated intracellular vesicles where the complex acts as a scaffold for cytoplasmic kinase assembly and signal transduction. Here we report that CXCR7 was elevated in the majority of prostate cancer (PCa) with neuroendocrine features (NEPC). CXCR7 markedly induced mitotic spindle and cell cycle gene expression. Mechanistically, we identified Aurora Kinase A (AURKA), a key regulator of mitosis, as a novel target that was bound and activated by the CXCR7-ARRB2 complex...

Despite substantial improvements in the treatment landscape of prostate cancer, the evolution of hormone therapy-resistant and metastatic prostate cancer remains a major cause of cancer-related death globally. The mainstay of treatment for advanced prostate cancer is targeting of androgen receptor signaling, including androgen deprivation therapy plus second-generation androgen receptor blockade (e.g., enzalutamide, apalutamide, darolutamide), and/or androgen synthesis inhibition (abiraterone). While these agents have significantly prolonged the lives of patients with advanced prostate cancer, is nearly universal...

The Aurora Kinase family (AKI) is composed of serine-threonine protein kinases involved in the modulation of the cell cycle and mitosis. These kinases are required for regulating the adherence of hereditary-related data. Members of this family can be categorized into aurora kinase A (Ark-A), aurora kinase B (Ark-B), and aurora kinase C (Ark-C), consisting of highly conserved threonine protein kinases. These kinases can modulate cell processes such as spindle assembly, checkpoint pathway, and cytokinesis during cell division...

Prostate cancer is one of the devastating diseases characterized by genetic changes leading to uncontrolled growth and metastasis of the cells of the prostate gland and affects men worldwide. Conventional hormonal and chemotherapeutic agents are effective in mitigating the disease if diagnosed at an early stage. All dividing eukaryotic cells require mitotic progression for the maintenance of genomic integrity in progeny populations. The protein kinases, upon activation and de-activation in an ordered fashion, lead to spatial and temporal regulation of the cell division process...

Clinical studies have shown that subsets of cancer patients achieve a significant benefit from Aurora kinase inhibitors, suggesting an urgent need to identify biomarkers for predicting drug response. Chromodomain-helicase-DNA-binding protein 1 (CHD1) is involved in chromatin remodeling, DNA repair, and transcriptional plasticity. Prior studies have demonstrated that CHD1 has distinct expression patterns in cancers with different molecular features, but its impact on drug responsiveness remains understudied...

Androgen deprivation therapy (ADT) is a systemic therapy for advanced prostate cancer (PCa). Although most patients initially respond to ADT, almost all cancers eventually develop castration resistance. Castration-resistant PCa (CRPC) is associated with a very poor prognosis, and the treatment of which is a serious clinical challenge. Accumulating evidence suggests that abnormal expression and activation of various kinases are associated with the emergence and maintenance of CRPC. Many efforts have been made to develop small molecule inhibitors to target the key kinases in CRPC...

Tumor breakthrough is driven by genetic or epigenetic variations which assist in initiation, migration, invasion and metastasis of tumors. Astrocyte elevated gene-1 (AEG-1) protein has risen recently as the crucial factor in malignancies and plays a potential role in diverse complex oncogenic signaling cascades. AEG-1 has multiple roles in tumor growth and development and is found to be involved in various signaling pathways of: (i) Ha-ras and PI3K/AKT; (ii) the NF-κB; (iii) the ERK or mitogen-activated protein kinase and Wnt or β-catenin and (iv) the Aurora-A kinase...

Androgen receptor signaling primarily influences both the normal growth and proliferation of the prostate gland and the development of prostatic carcinoma. While localized prostate cancers are typically managed with definitive therapies like surgery and radiotherapy, many patients have recurrences in the form of metastatic disease. Androgen deprivation therapy, by way of castration via orchiectomy or with drugs like luteinizing hormone-releasing hormone (commonly called gonadotropin-releasing hormone) agonists and luteinizing hormone-releasing hormone antagonists, is the primary mode of therapy for advanced castration-sensitive prostate cancer...

Long non-coding RNAs (lncRNAs) play regulatory role in cellular processes and their aberrant expression may drive cancer progression. Here we report the function of a lncRNA PAINT (Prostate Cancer Associated Intergenic Non-Coding Transcript) in promoting prostate cancer (PCa) progression. Upregulation of PAINT was noted in advanced stage and metastatic PCa. Inhibition of PAINT decreased cell proliferation, S-phase progression, increased expression of apoptotic markers, and improved sensitivity to docetaxel and Aurora kinase inhibitor VX-680...

BACKGROUND: The aim of this study was to identify novel genes in promoting primary prostate cancer (PCa) progression and to explore its role in the prognosis of prostate cancer. METHODS: Four microarray datasets containing primary prostate cancer samples and benign prostate samples were downloaded from Gene Expression Omnibus (GEO), then differentially expressed genes (DEGs) were identified by R software (version 3.6.2). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed to identify the function of DEGs...

Aurora-A kinase plays a central role in mitosis, where aberrant activation contributes to cancer by promoting cell cycle progression, genomic instability, epithelial-mesenchymal transition, and cancer stemness. Aurora-A kinase inhibitors have shown encouraging results in clinical trials but have not gained Food and Drug Administration (FDA) approval. An innovative computational workflow named Docking-based Comparative Intermolecular Contacts Analysis (dbCICA) was applied-aiming to identify novel Aurora-A kinase inhibitors-using seventy-nine reported Aurora-A kinase inhibitors to specify the best possible docking settings needed to fit into the active-site binding pocket of Aurora-A kinase crystal structure, in a process that only potent ligands contact critical binding-site spots, distinct from those occupied by less-active ligands...

Resistance to androgen-receptor (AR) directed therapies is, among other factors, associated with Myc transcription factors that are involved in development and progression of many cancers. Overexpression of N-Myc protein in prostate cancer (PCa) leads to its transformation to advanced neuroendocrine prostate cancer (NEPC) that currently has no approved treatments. N-Myc has a short half-life but acts as an NEPC stimulator when it is stabilized by forming a protective complex with Aurora A kinase (AURKA). Therefore, dual-inhibition of N-Myc and AURKA would be an attractive therapeutic avenue for NEPC...

SPOP, an adaptor protein for E3 ubiquitin ligase can function as a tumor-suppressor or a tumor-enhancer. In castration-resistant prostate cancer (CRPC), it inhibits tumorigenesis by degrading many oncogenic targets, including androgen receptor (AR). Expectedly, SPOP is the most commonly mutated gene in CRPC (15%), which closely correlates with poor prognosis. Importantly, 85% of tumors that retain wild-type SPOP show reduced protein levels, indicating that SPOP downregulation is an essential step in CRPC progression...

Therapy-induced neuroendocrine prostate cancer (NEPC), an extremely aggressive variant of castration-resistant prostate cancer (CRPC), is increasing in incidence with the widespread use of highly potent androgen receptor (AR)-pathway inhibitors (APIs) such as Enzalutamide (ENZ) and Abiraterone and arises via a reversible trans-differentiation process, referred to as neuroendocrine differentiation (NED). The molecular basis of NED is not completely understood leading to a lack of effective molecular markers for its diagnosis...

Multifunctional protein YBX1 upregulation promotes castration-resistant prostate cancer (CRPC). However, YBX1 protein abundance, but not its DNA status or mRNA levels, predicts CRPC recurrence, although the mechanism remains unknown. Similarly, the mechanism by which YBX1 regulates androgen receptor (AR) signaling remains unclear. We uncovered the first molecular mechanism of YBX1 upregulation at a post-translational level. YBX1 was identified as an Aurora Kinase-A (AURKA) substrate using a chemical screen...

Hypoxia is a major factor in tumor progression and resistance to therapies, which involves elevated levels of the transcription factor HIF-1a. Here we report that prostate tumor xenografts express high levels of HIF-1a and show greatly enhanced growth in response to knockdown of the E3 ligase CHIP (C-terminus of Hsp70-interacting protein). In multiple human prostate cancer cell lines under hypoxia taxol treatment induces the degradation of HIF-1a and this response is abrogated by knockdown of CHIP, but not by E3 ligase VHL or RACK1...