MK-5108 / Vertex, Merck (MSD) - LARVOL DELTA

Targeting Aurora A kinase: Computational discovery of potent inhibitors through integrated pharmacophore and simulation approaches. (PubMed, Comput Biol Chem) - "Screening of the ZINC database yielded 774 hits, from which A1 (ZINC63106872) and A2 (ZINC39272872) were identified as the top candidates, with superior docking scores (-9.24 and -8.97 kcal/mol) compared to the reference MK-5108 (-7.49 kcal/mol)...RMSF values remained below 2.4 Å. The most favourable binding energy for A1 (-75.34 kcal/mol) in MM-GBSA analysis confirms its strong interaction and therapeutic potential."

Journal • CNS Disorders • Oncology • AURKA

Combination of AURKA inhibitor and MEK inhibitor strongly enhances G1 arrest and induces synergistic antitumor effect on KRAS or BRAF mutant colon cancer cells. (PubMed, Biochem Biophys Rep) - "In conclusion, the combination of MK-5108 and trametinib may synergistically inhibit tumor cell division with or without TP53 mutation, and with either KRAS or BRAF mutation. Furthermore, the combination therapy could be more effective in wild-type TP53 cells."

Journal • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • BRAF • KRAS

System biology based drug repositioning approach identifies drug candidates for pancreatic ductal adenocarcinoma (SITC 2024) - "Employing our systematic drug repositioning approach, we identified AVL-292 and MK-5108 as promising candidates for PDAC treatment. Additional experimental validation confirmed that these compounds significantly inhibited cell motility, suggesting potential therapeutic benefits. Conclusions Our study demonstrates the feasibility and efficacy of a network-based drug repositioning approach in identifying potential drugs for the treatment of PDAC."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

EZH2 as a prognostic-related biomarker in lung adenocarcinoma correlating with cell cycle and immune infiltrates. (PubMed, BMC Bioinformatics) - "Highly expressed EZH2 is a predictor of a suboptimal prognosis in LUAD and may serve as a prognostic marker and target gene for LUAD. The underlying cause may be associated with the synergistic effect of KRAS, immune cell infiltration, and metabolic processes."

Biomarker • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • EGFR • EZH2 • KRAS

First Report of Root Rot Caused by Pythium myriotylum on Sesame in China. (PubMed, Plant Dis) - "GenBank BLAST search identified the sequences as P. myriotylum ITS and COI sequences (e.g., HQ237488.1 and MK510848.1, respectively) with 100% coverage and 100% identity...Once the disease breaks out in a large area, the yield of sesame will be seriously threatened. The results provide important implications for the prevention and management of this disease."

Journal

Non-canonical NLRC4 inflammasomes in astrocytes contribute to glioma malignancy. (PubMed, Inflamm Res) - "The findings of this study suggest that non-canonical NLRC4 inflammasomes contribute to poor prognosis in patients with glioma and induce an inflammatory microenvironment. We propose the pathological phenomenon of non-canonical NLRC4 inflammasomes and several therapeutic strategies based on the modulation of the inflammatory tumor microenvironment."

Journal • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • NF-κβ

Targeted AURKA degradation: Towards new therapeutic agents for neuroblastoma. (PubMed, Eur J Med Chem) - "We present a structure-activity relationship (SAR) study of MK-5108-derived PROTACs against AURKA by exploring different linker lengths and exit vectors on the thalidomide moiety. Furthermore, altering the attachment point of the PEG linker to the 5-position of thalidomide allowed us to identify a potent AURKA degrader with a linker as short as 2 PEG units. With this, our SAR-study provides interesting lead structures for further optimization and validation of AURKA degradation as a potential therapeutic strategy in neuroblastoma."

Journal • CNS Tumor • Neuroblastoma • Neuroendocrine Tumor • Oncology • Solid Tumor • Targeted Protein Degradation • AURKA • MYCN

AML-377 A "Designed" High-Throughput Drug Screening Strategy Identifies Aurora Kinase A Inhibitors as Promising Preclinical Candidates for the Treatment of NPM1-Mutated AML. (PubMed, Clin Lymphoma Myeloma Leuk) - "We demonstrated that using HTS can considerably shorten drug discovery time scales, leading to the identification of promising lead compounds. Our study is the first to provide preclinical evidence of the antileukemic activity of AURKAi, with particular focus on NPM1-mutated AML."

Journal • Preclinical • Acute Myelogenous Leukemia • CNS Disorders • Hematological Malignancies • Leukemia • Oncology • Psychiatry • AURKA • NPM1

A “Designed” High-Throughput Drug Screening Strategy Identifi es Aurora Kinase A Inhibitors as Promising Preclinical Candidates for the Treatment of NPM1-Mutated AML (SOHO 2022) - "In the validation assay, 2 compounds (MK-5108 and MK-8745) were confi rmed as more active against NPM1-mutated than NPM1–wild-type AML cells by either CyQUANT or apoptosis assay. Strikingly, we confi rmed selectivity for two additional AURKAi (Alisertib and ENMD-2076, both isoform-selective inhibitors of AURKA) that were not included in the screening library... We demonstrated that using HTS can considerably shorten drug discovery time scales, leading to the identifi cation of promising lead compounds. Our study is the fi rst to provide preclinical evidence of the antileukemic activity of AURKAi, with particular focus on NPM1-mutated AML."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • AURKA • NPM1

Apoptosis is responsible for the cytotoxic effects of anti-GD2 ganglioside antibodies and aurora A kinase inhibitors on human neuroblastoma cells. (PubMed, Acta Biochim Pol) - "However, the presence of necroptosis was ruled out in MK-5108-treated IMR-32 and CHP-134 cells. In summary, the effects of the combination of ch14.18/CHO mAb and aurora A kinase inhibitors (MK-5108 and MK-8745) were shown to enhance apoptosis in IMR-32 cells compared to when used individually."

IO biomarker • Journal • Neuroblastoma • Oncology • Solid Tumor • AURKA • CASP3 • CASP7

Development of potent dual PDK1/AurA kinase inhibitors for Ewing sarcoma therapy (AACR 2022) - "OSU-03012 (PDK-1 inhibitor) and MK-5108 (AurA inhibitor) were used as reference compounds.Results. Data Brief 29 (2020) 105206.[2] Sistito S. et al. Eu J Med Chem 226 (2021) 11389."

Colon Cancer • Colorectal Cancer • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • AURKA • EGFR • KRAS • PTEN • RB1 • RPS6KA3 • TP53

Screening for Inhibitors of YAP Nuclear Localization Identifies Aurora Kinase A as a Modulator of Lung Fibrosis. (PubMed, Am J Respir Cell Mol Biol) - "In addition, MK-5108 treatment reduced lung collagen deposition in the bleomycin mouse model of pulmonary fibrosis. Our results reveal a novel role for AURKA in YAP-mediated profibrotic activity in fibroblasts and highlight the potential of small-molecule screens for YAP inhibitors for identification of novel agents with anti-fibrotic activity."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • AURKA • AURKB • LATS1 • LATS2

Blocking AURKA with MK-5108 attenuates renal fibrosis in chronic kidney disease. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "In this study, inhibition of AURKA by MK-5108 markedly attenuated renal fibrosis. MK-5108 is a potential therapeutic agent for treatment of renal fibrosis in CKD."

Journal • Chronic Kidney Disease • Fibrosis • Immunology • Nephrology • Oncology • Renal Disease • AURKA • TGFB1

[VIRTUAL] A YAP Inhibitor Screen Identifies the Aurora Kinase A Inhibitor MK-5108 as a Modulator of Lung Fibrosis (ATS 2021) - "Furthermore, MK-5108 treatment of mice reduces lung collagen deposition in the bleomycin mouse model of pulmonary fibrosis. Our results again highlight the potential of small-molecule screens for YAP inhibitors and reveal novel antifibrotic activity of an Aurora kinase A inhibitor."

Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Respiratory Diseases • AURKA • AURKB

[VIRTUAL] Dual targeting of PDK1 and Aurora A using first-in class OXID-pyridonyl compounds in preclinical models of Ewing sarcoma (AACR 2021) - "OSU-03012 (PDK1 inhibitor) and MK-5108 (AurA inhibitor) were used as reference compounds to investigate the functional crosstalk between the two pathways in sensitive cancer cell lines.Results. Here we report the characterization of two potent first-in-class dual PDK1-AurA inhibitors, SA16 and VI8. Our findings suggest that innovative PDK1/AurA dual-target molecules which could represent an attractive lead scaffold for the design and synthesis of a new multitarget strategy for Ewing sarcoma."

Preclinical • Colon Cancer • Colorectal Cancer • Ewing Sarcoma • Glioblastoma • Oncology • Sarcoma • Solid Tumor • AURKA • CDK1 • CDKN1A • EGFR • KRAS • MYC • PDPK1 • PTEN • RB1 • TP53

ID1 overexpression promotes HCC progression by amplifying the AURKA/Myc signaling pathway. (PubMed, Int J Oncol) - "However, the effects of ID1 were markedly reversed by the AURKA inhibitor VX689 and the Myc inhibitor 10058‑F4...Increased AURKA expression subsequently enhanced Myc expression at both transcriptional and post‑transcriptional level, leading to amplification of the Myc oncogenic signaling pathway. This novel ID1/AURKA/Myc axis could be a promising therapeutic target for the development of effective therapeutic strategies for advanced HCC."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • AURKA • CDH1

A screening method for the identification of potentially effective drug-drug combinations reveals a synergistic interaction between Aurora-A inhibitor MK-5108 and Bcl-xL inhibitor navitoclax (AACR-NCI-EORTC 2013) - Abstract #A104; Presentation time: Sunday, Oct 20, 2013, 12:30 PM - 3:00 PM; "Synergistic interactions were observed with the combination of an Aurora-A inhibitor, MK-5108, with navitoclax, an inhibitor of Bcl-2 family survival proteins....Several features emerged from this analysis including the observation that Bcl-xL expression levels predict resistance to the single agent Aurora-A inhibitor and to synergy of combined MK-5108 and navitoclax."

Preclinical • Oncology

A screening-based approach identifies cell cycle regulators AURKA, CHK1 and PLK1 as targetable regulators of chondrosarcoma cell survival. (PubMed, J Bone Oncol) - "Dose response curves were performed using tyrosine kinase inhibitors: MK-5108 (AURKA), LY2603618 (CHK1) and Volasertib (PLK1) using viability assays and cell cycle analysis. AURKA, CHK1 and PLK1 are identified as important survival genes in chondrosarcoma cell lines. Although further research is needed to validate these findings, inhibiting CHK1 seems to be the most promising potential therapeutic target for patients with chondrosarcoma."

Journal • AURKA • CASP3 • CHEK1

GD2 ganglioside-binding antibody 14G2a and specific aurora A kinase inhibitor MK-5108 induce autophagy in IMR-32 neuroblastoma cells. (PubMed, Apoptosis) - "Application of a lysosomotropic agent-chloroquine (CQ) affected the 14G2a mAb- and MK-5108-stimulated autophagic flux. Most importantly, we showed that interfering with autophagy at its early and late step augments the 14G2a mAb-induced apoptosis, therefore we can conclude that inhibition of autophagy is the primary mechanism of the CQ-mediated sensitization to the 14G2a mAb-induced apoptosis. Although, there was no virtual stimulation of autophagy in the 14G2a mAb-treated CHP-134 neuroblastoma cells, we were able to show that PHLDA1 protein positively regulates autophagy and this process exists in a mutually exclusive manner with apoptosis in PHLDA1-silenced CHP-134 cells."

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