tozasertib (MK-0457) / Vertex, Merck (MSD) - LARVOL DELTA

Identification of glycolysis-related gene signatures for prognosis and therapeutic targeting in idiopathic pulmonary fibrosis. (PubMed, Front Pharmacol) - "A bleomycin (BLM)-induced pulmonary fibrosis mouse model was used for experimental validation via reverse transcription-quantitative polymerase chain reaction (RT-qPCR)...Drug prediction identified inhibitors (such as Tozasertib for AURKA, Plerixafor for CXCR4) as potential therapeutic agents...Notably, AURKA, MERTK, and CXCR4 were associated with pathways linked to fibrosis progression and represent potential therapeutic targets. Our findings provide insights into metabolic reprogramming in IPF and suggest that targeting glycolysis-related pathways may offer novel pharmacological strategies for antifibrotic therapy."

Gene Signature • Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • AGRN • AURKA • CXCR4 • DEPDC1 • MERTK • PFKM • PLOD2 • SDC1 • TPBG

Unraveling the molecular landscape of non-small cell lung cancer: Integrating bioinformatics and statistical approaches to identify biomarkers and drug repurposing. (PubMed, Comput Biol Med) - "Finally, seven repurposed candidate drugs ENTRECTINIB, SORAFENIB, CHEMBL1765740, TOZASERTIB, NERVIANO, AZD-1152-HQPA, and SELICICLIB were proposed through molecular docking analysis. In conclusion, the findings of this study have the potential to significantly impact the early diagnosis, prognosis, and treatment of NSCLC."

Biomarker • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AURKA • CCNA2 • CCNB1

Immune regulatory genes impact the hot/cold tumor microenvironment, affecting cancer treatment and patient outcomes. (PubMed, Front Immunol) - "Finally, dasatinib and tozasertib were identified as drug candidates capable of converting cold pancreatic adenocarcinoma tumors into hot tumors. In this study, we developed a framework for discerning clinically significant immune subtypes across various cancer types, further identifying several potential targets for converting cold tumors into hot tumors to enhance anticancer treatment efficacy."

Biomarker • IO biomarker • Journal • Bladder Cancer • Cervical Cancer • Cervical Squamous Cell Carcinoma • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • Squamous Cell Carcinoma • Urothelial Cancer • CD276 • CD73 • CD8 • NT5E • PD-1

A Novel BCR::ABL1 Rearrangement Harboring the Gatekeeper Mutation Drives Hyper-Kinase Activity Conferring Resistance to Ponatinib and Asciminib Combination Therapy (ASH 2024) - "These cell lines were subjected to dose-dependent proliferation assays with type-I (bosutinib, dasatinib, VX680, and BIRB796), type-II (imatinib, nilotinib, ponatinib, and ribastinib), and type-IV (asciminib) inhibitors. Interestingly, BCR : : ABL1b6a3 showed increased sensitivity to type-I inhibitors, yet all clinical type-I inhibitors are ineffective against T315I and other gatekeeper variants. Therefore, developing gatekeeper-selective type-I inhibitor is crucial to overcome clinical resistance."

Combination therapy • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • BCR

Molecular simulations and machine learning methods for the identification of novel aurora A kinase inhibitors. (PubMed, J Biomol Struct Dyn) - "Both docking studies revealed perfect binding of all identified ligands in active site pockets of AAK protein with similar amino acids of active sites as compared with standard BindingDB_50433632 compound and co-crystal ligand VX-680 binding mode of AAK protein. Therefore, it can be concluded that computational drug discovery approaches are meticulously implemented to identify potential AAKs inhibitors/modulators, and credential of the work was substantiated through the identification of three potential AAKs inhibitors/modulators that may hold significant promise for improving cancer management, however, need extensive biological assays or pre-clinical trials for assessing the efficacy profile of the identified compounds."

Journal • Machine learning • Oncology • AURKA

Prognosis and immunotherapeutic implications of molecular classification of cervical cancer based on immunophenoscore-related genes. (PubMed, J Biomol Struct Dyn) - "cluster2 had higher immune cell infiltration levels and better prognosis, with greater sensitivity to Cyclopamine, Imatinib, MG-13, Paclitaxel, PHA-665752, Rapamycin, Sorafenib, Sunitinib, and VX-680. In contrast, cluster3 had higher TTN and PIK3CA mutations and greater sensitivity to AZ628, Dasatinib, Doxorubicin, HG-6-64-1, JQ12, Midostaurin, PF-562271, TAE684, and WH-4-023. In conclusion, we developed a feasible risk score model based on IPS-related genes for cervical cancer prognosis and identified potential drugs for different cervical cancer subtypes."

IO biomarker • Journal • Cervical Cancer • Oncology • Solid Tumor • PD-L2 • PIK3CA

Establishment and validation of the prognostic risk model based on the anoikis-related genes in esophageal squamous cell carcinoma. (PubMed, Ann Med) - "The IC50 values of predicted drugs, in the case of Tozasertib 1096 and WIKI4 1940, were significantly variant between risk groups...The study established an ARG prognosis model of ESCC. It provided a reference for the research of ARGs in ESCC."

Biomarker • Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • LAMC2 • TNFSF10

Differential regulation of expression of the protein kinases DYRK1A and DYRK1B in cancer cells. (PubMed, Sci Rep) - "Consistently, AURK inhibitors VX-680 (tozasertib), MLN8237 (alisertib), AZD1152-HQPA (barasertib) resulted in the upregulation of DYRK1B expression in A549 cells. In summary, our findings indicate that the expression of DYRK1A and DYRK1B is differentially regulated in cancer cells and reveal that the kinase inhibitor XMU-MP-1 increases DYRK1B expression likely through off target inhibition of Aurora kinases."

Journal • Oncology • AURKA • AURKB • DYRK1A • DYRK1B

TARGETED ANTI-CANCER DRUG DELIVERY IN NEUROBLASTOMA (SIOP 2024) - "In this study, the suppression of MYCN expression and protein levels, as well as cellular death, were examined by encapsulating the Aurora inhibitor Tozasertib (TOZA) and the mTOR inhibitor Everolimus (EVER) in NPs, targeted with NB-specific Anti-GD2...Dinutuximab-β (DTX-β) was used for surface modification... The cytotoxic effect of DTX-β/EVER-TOZA@PEG-b-PLGA in cells significantly reduced tumor sizes in mice. Our in vitro and in vivo animal model findings support the potential of DTX-β/EVER-TOZA@PEG-b-PLGA combination as a candidate in vivo therapeutic agent for NB."

CNS Tumor • Embryonal Tumor • Neuroblastoma • Oncology • Solid Tumor • MYCN

Construction and validation of a necroptosis-related prognostic signature in acute myeloid leukemia. (PubMed, Medicine (Baltimore)) - "Besides, we found that the BIRB0796, VX680, Vorinostat, and Axitinib positively related with NRG score, whereas CI. CHO, and AZD6244 negatively correlated with the NRG score. These drugs may provide a reference for subsequent treatment."

Biomarker • IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

In Vitro Assessment of Inhibitory Effects of Kinase Inhibitors on CYP2C9, 3A and 1A2: Prediction of Drug-Drug Interaction Risk with Warfarin and Direct Oral Anticoagulants. (PubMed, Eur J Pharm Sci) - "Our results suggest that several kinase inhibitors, including vatalanib and linsitinib, can cause CYP-mediated drug-drug interactions with warfarin and, to a lesser extent, with apixaban and rivaroxaban. The work provides mechanistic insights into the risk of DDIs between kinase inhibitors and anticoagulants, which can be used to avoid preventable DDIs in the clinic."

Journal • Preclinical • CYP2C9

Small Molecule-Induced Post-Translational Acetylation of Catalytic Lysine of Kinases in Mammalian Cells. (PubMed, J Am Chem Soc) - "In order to demonstrate that this strategy was capable of target-selective and reversible chemical acetylation of protein kinases, we further developed six acetylating compounds on the basis of VX-680 (a noncovalent inhibitor of AURKA)...Finally, the reversible Ac13-induced acetylation of endogenous AURKA was demonstrated in SIRT3-transfected HCT116 cells. By disclosing the first cell-active acetylating compounds capable of both global and target-selective post-translational acetylation of the catalytic lysine on kinases, our strategy could provide a useful chemical tool in kinase biology and drug discovery."

Journal • AURKA • SIRT3

A One-Step Green Microwell Spectrophotometric Assay for the Determination of Certain New Chemotherapeutic Drug Formulations. (PubMed, J AOAC Int) - "The assay is useful for routine analysis of drugs in their formulations in quality control laboratories."

Journal • Oncology

Screening of potential drugs for the treatment of diabetic kidney disease using single-cell transcriptome sequencing and connectivity map data. (PubMed, Biochem Biophys Res Commun) - "This strategy based on single-cell transcriptome sequencing and CMap data can facilitate the identification and aid the rapid development of clinical DKD drugs. Paroxetine, screened by this strategy, has excellent renoprotective effects."

Journal • Diabetic Nephropathy • Fibrosis • Immunology • Inflammation • Nephrology • Renal Disease • NFE2L2 • NLRP3

Integrative analysis of senescence-related genes identifies robust prognostic clusters with distinct features in hepatocellular carcinoma. (PubMed, J Adv Res) - "Our findings provide insights into the role of SRGs in patients stratification and precision medicine."

Journal • Gastrointestinal Cancer • Gene Therapies • Hepatocellular Cancer • Oncology • Solid Tumor

A novel anoikis-related gene signature predicts prognosis in patients with sepsis and reveals immune infiltration. (PubMed, Sci Rep) - "Moreover, tozasertib had low binding energy with CXCL8, CFLAR, FASLG and TP53, and would be a potential compound for sepsis. Conclusively, our results identified a new prognostic model and potential therapeutic molecular for sepsis, providing new insights on mechanism and treatment of sepsis."

Gene Signature • Journal • Infectious Disease • Septic Shock • CFLAR • CXCL8 • FASLG • TP53

Global Reactivity Profiling of the Catalytic Lysine in Human Kinome for Covalent Inhibitor Development. (PubMed, Angew Chem Int Ed Engl) - "By further introducing these aminophiles into VX-680 (a noncovalent inhibitor of AURKA kinase), we generated novel lysine-reactive TCIs that exhibited excellent in vitro potency and reasonable cellular activities with prolonged residence time. Our work serves as a general guide for the development of lysine-reactive ArOSO2F-based TCIs."

Journal • AURKA

Tozasertib activates anti-tumor immunity through decreasing regulatory T cells in melanoma. (PubMed, Neoplasia) - "Single-cell analysis revealed that AURKB suppressed anti-tumor immunity by increasing MIF-CD74/CXCR4 signaling between tumor cells and lymphocytes. Our study suggests that AURKB is a newly identified anti-tumor immunity suppressor, whose inhibitors may be developed as novel anti-tumor immunity drugs and may have synergistic anti-melanoma effects with immune checkpoint therapies."

Journal • Melanoma • Oncology • Solid Tumor • AURKB • CD4 • CD74 • CD8

High spindle and kinetochore-associated complex subunit-3 expression predicts poor prognosis and correlates with adverse immune infiltration in hepatocellular carcinoma. (PubMed, World J Gastrointest Surg) - "High SKA3 expression led to poor prognosis in patients with HCC by enhancing HCC proliferation and repressing immune cell infiltration surrounding HCC. SKA3 may be used as a biomarker for poor prognosis and as a therapeutic target in HCC."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • CD8

Stratification of Tamoxifen Synergistic Combinations for the Treatment of ER+ Breast Cancer. (PubMed, Cancers (Basel)) - "In this study, we discovered two tamoxifen combination therapies, with simeprevir and VX-680, that reduce the tumor burden in animal models of ER+ breast cancer more than either compound or tamoxifen alone. Additionally, these tamoxifen combinations reduced the expression of HER2, a hallmark of tamoxifen treatment, which can facilitate acquisition of a treatment-resistant phenotype. These combinations could provide clinical benefit by potentiating tamoxifen treatment in ER+ breast cancer."

Journal • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

The characteristics of metabolic related pathways under different anoikis activities revealed by pan-cancer analyses. (ASCO 2023) - "Drug efficacy analysis revealed that BCL2 gene was significantly associated with sensitive drug response on Venetoclax, ABT737, and Tozasertib. The characteristics of anoikis activities and metabolic related pathways during tumor progression were comprehensively studied and the prognosis value of anoikis was further assessed by drug efficacy."

Pan tumor • Oncology • Thymus Cancer • BCL2 • BRCA • CAV1 • CD4 • CD8

The feedback loop of AURKA/DDX5/TMEM147-AS1/let-7 drives lipophagy to induce cisplatin resistance in epithelial ovarian cancer. (PubMed, Cancer Lett) - "Platinum-taxane chemotherapy is the first-line standard-of-care treatment administered to patients with epithelial ovarian cancer (EOC), and faces the major challenge of cisplatin resistance. Our mathematical model shows that the feedback loop has the potential to act as a biological switch to maintain on- (activated) or off- (deactivated) status, implying the possible resistance of single use of VX-680 or TMEM147-AS1 siRNA. The combined use reduces both the protein level of AURKA using TMEM147-AS1 siRNA and its kinase activity using VX-680, showing more significant effect than the use of TMEM147-AS1 siRNA or VX-680 alone, which provides a potential strategy for EOC treatment."

Journal • Oncology • Ovarian Cancer • Solid Tumor • AURKA • DDX5 • MIRLET7B

Overexpression of TREM1 is Associated with the Immune-Suppressive Microenvironment and Unfavorable Prognosis in Pan-Cancer. (PubMed, J Inflamm Res) - "Through connective map analysis, therapeutically potential compounds like tozasertib and TPCA-1 were identified, which can be used synergistically with immunotherapy to improve the poor prognosis of patients with high TREM1 levels. Through a systematic and comprehensive pan-cancer analysis, we demonstrated that overexpression of TREM1 in tumors correlated closely with unfavorable outcome, infiltration of immune-suppressive cells, and immune regulation, which highlights its potential use as a tumor prognostic biomarker and a novel target for immunotherapy."

IO biomarker • Journal • Pan tumor • Genito-urinary Cancer • Immune Modulation • Oncology • Renal Cell Carcinoma • Solid Tumor • CD8

Comprehensive genomics analysis of aging related gene signature to predict the prognosis and drug resistance of colon adenocarcinoma. (PubMed, Front Pharmacol) - "Low risk patients were more sensitive to small molecule drugs including Erlotinib, Sunitinib, MG-132, CGP-082996, AZ628, Sorafenib, VX-680, and Z-LLNle-CHO. Four risk genes (CALB1, CPA3, NOXA1, and TNNT1) had significant positive correlation with their methylation level, while six genes (CCL22, GPRC5B, HSPA1A, MFNG, PABPC1L, and PCOLCE2) were negatively correlated with their methylation level. This study provides novel understanding of heterogeneity in COAD from the perspective of senescence, and develops signatures for prognosis prediction in COAD."

Gene Signature • IO biomarker • Journal • Tumor mutational burden • Colon Cancer • Colorectal Adenocarcinoma • Gastrointestinal Cancer • Oncology • CALB1 • CCL2 • CCL22 • CPA3 • HSPA1A • PABPC1L • TMB

2-Phenoxy-3, 4'-bipyridine derivatives inhibit AURKB-dependent mitotic processes by disrupting its localization. (PubMed, Eur J Med Chem) - "Hierarchical clustering of cell fitness profiles reveals that these compounds cluster with each other, rather than with known AURK inhibitors such as AMG900 and VX-680. The discovery and optimization of compounds that disrupt AURKB localization are successfully facilitated by MIPS. Our findings suggest that 2-phenoxy-3, 4'-bipyridine derivatives have the potential to be further developed as effective therapeutics for the treatment of malignancy by delocalizing AURKB."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AURKB