MLN8054 / Takeda - LARVOL DELTA

Deciphering Shared Gene Signatures and Immune Infiltration Characteristics Between Gestational Diabetes Mellitus and Preeclampsia by Integrated Bioinformatics Analysis and Machine Learning. (PubMed, Reprod Sci) - "In addition, the research also identified four potential therapeutic compounds for GDM (prima-1-met, geranylgeraniol, MLN-8054, and LY-364947), along with other drugs (deferiprone, peucedanin, MPEP, and IWR-1-endo) that could be targeted for treating PE. Moreover, we investigated the similarities and differences between the two diseases in terms of immune infiltration landscape and analyzed the correlations between key genes and the immune infiltration landscape, which provided insights into the molecular mechanisms underlying the development of GDM and PE. This understanding could pave the way for breakthroughs in identifying new immunotherapeutic targets and strategies for disease prevention and treatment."

Gene Signature • IO biomarker • Journal • Diabetes • Gestational Diabetes • Gynecology • Infectious Disease • Metabolic Disorders • MIR204 • MIR205 • MIR23A • MIR455

GFLearn: Generalized Feature Learning for Drug-Target Binding Affinity Prediction. (PubMed, IEEE J Biomed Health Inform) - "Additionally, cross-dataset evaluations and noise perturbation experiments further validated the model's generalizability across different data distributions. Case studies on two drug-target pairs, Canertinib-PIK3C2G and MLN8054-FLT1, provided further evidence of GFLearn's ability to make accurate binding affinity predictions, offering valuable insights for drug screening and repurposing efforts."

Journal • FLT1

Helicobacter pylori VacA-induced mitochondrial damage in the gastric pit cells of the antrum and therapeutic rescue. (PubMed, Biomaterials) - "MLN8054 was effective in VacA-treated and Hp-infected hAGOs and mice, highlighting hAGOs as a promising drug-screening model. These findings suggest that mitochondrial quality control may serve as a promising therapeutic target for Hp VacA-mediated toxicity and disease progression."

Journal • Infectious Disease • Metabolic Disorders • AURKA

Drugging the undruggable: Towards SNIPERs and covalent molecular glue degraders of aurora kinase A as indirect degraders of N-Myc and c-Myc (ACS-Fall 2024) - "Building on recent publications of the discovery of AURKA proteolysis-targeting chimeras (PROTACs) that carry thalidomide as the E3 ligase-targeting ligand, and thus recruit AURKA to CEREBLON, we have linked the AUKRA inhibitor alisertib (MLN8054) to IAP inhibitors – the inhibitors of apoptosis proteins (IAPs) also belong to the E3 ubiquitin ligase family – affording specific and nongenetic IAP-dependent protein erasers, or SNIPERs. In addition, towards the development of a covalent molecular glue of AURKA, we have grafted onto alisertib the motif EST1060, a fumarate-based Michael acceptor that is reported to react with a cysteine thiol on the surface of the E3 ligase RNF126. We will report our progress on the discovery of targeted degraders of AURKA, and, by association, indirect degraders of N-Myc and c-Myc."

Oncology • Targeted Protein Degradation • AURKA • CRBN • MYC • MYCN

PRIMARY CILIA OF SYSTEMIC SCLEROSIS (SSC) DERMAL FIBROBLASTS ARE DISRUPTED BY DOWNREGULATION OF CAVEOLIN-1 AND ABERRANT ACTIVITY OF AURORA A KINASE, INDEPENDENT OF TRANSFORMING GROWTH FACTOR BETA (SSWC 2024) - "Fibroblasts were treated with exogenous TGFβ, TGFβR1 inhibitor SD208, ROCK2 inhibitor KD025, and Aurora A kinase (AURKA) inhibitor MLN8054... PC length is stably reduced in SSc dermal fibroblasts, early in disease, with Caveolin-1 downregulation and aberrant AURKA activity contributing to the shorter cilium. While TGFβ activation can shorten PC via a non-canonical pathway involving ROCK2, this is not responsible for the short cilia phenotype in SSc. These findings support the notion that SSc profibrotic activation may involve mechanisms beyond TGFβ, and highlight the potential significance of Caveolin-1 and AURKA in modulating PC length as contributors to profibrotic activation, and potential therapeutic targets for tissue fibrosis."

Fibrosis • Systemic Sclerosis • AURKA • CAV1 • SMAD3

Systemic Sclerosis (SSc) Dermal Fibroblasts Show Shortened Primary Cilia Due to Aberrant Aurora a Kinase Activation Independently of Transforming Growth Factor β Signalling (ACR Convergence 2023) - "SD208 (1µM) was used to inhibit TGFß Receptor Kinase 1 (TGFßR1), MLN8054 (5µM) was used to inhibit Aurora A Kinase (AURKA), and Tubastatin A (1µM) was used to inhibit Histone Deacetylase 6 (HDAC6)... PC length is stably reduced in SSc dermal fibroblasts independently of TGFßR1 activity. Inhibition of AURKA in SSc restores "healthy" PC length via an atypical mechanism not involving its primary effector HDAC6. These observations support the notion that the profibrotic activation of dermal fibroblasts in SSc may go beyond a TGFß-dependent mechanism."

Fibrosis • Immunology • Scleroderma • Systemic Sclerosis • AURKA

Phenotypic profiling of Aurora inhibitors using the OncoPanelTMplatform (AACR 2023) - "Activity of the AurA-selective inhibitor, MLN8054, was also evaluated in the Eurofins Discovery BioMAP® Diversity PLUS human primary cell phenotypic profiling service to give a broader view of its biological activity. These studies demonstrate the combined value of using the OncoPanel and BioMAP platforms to determine mechanistic, functional, and broader biological activity of therapeutic candidates in relevant cellular models for a better translational understanding of potential therapeutic capabilities and accelerate decision-making."

Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • CASP3

Phosphorylation, Mg-ADP, and Inhibitors Differentially Shape the Conformational Dynamics of the A-Loop of Aurora-A. (PubMed, Biomolecules) - "In the closed states, binding of CD532 and MLN8054 inhibitors has the effect of increasing the distance of the N- and C-lobes of the kinase domain of Aurora-A, and the angle analysis between those two lobes during MD simulations showed that the N- and C-lobes are kept more open in presence of CD532, compared to MLN8054. As the A-loop is a common feature of Aurora protein kinases, our studies provide a general description of the conformational dynamics of this structure upon phosphorylation and different ligands binding."

Journal • FCGR2A • FCGR2B

Integrating Differential Gene Expression Analysis with Perturbagen-Response Signatures May Identify Novel Therapies for Thyroid-Associated Orbitopathy. (PubMed, Transl Vis Sci Technol) - "TAO OASC cell lines were treated in vitro with six identified small molecules (Torin-2, PX12, withaferin A, isoliquiritigenin, mitoxantrone, and MLN8054), and expression of key adipogenic and differentially expressed genes was measured with quantitative polymerase chain reaction after 7 days of treatment. Combining disease expression signatures with LINCS small molecule prediction software can identify promising preclinical drug candidates for TAO. These findings may offer insight into future potential therapeutic options for TAO and demonstrate a streamlined model to predict drug candidates for other diseases."

Journal • Ocular Infections • Ophthalmology • FABP4

Molecular dynamics and free energy studies on Aurora kinase A and its mutant bound with MLN8054: insight into molecular mechanism of subtype selectivity (Mol Biosyst) - The residue Glu177 in Aurora-B displays electrostatic repulsion with MLN8054, while the corresponding Thr217 in Aurora-A has favorable interactions with MLN8054; The conformation change & the difference between the binding

Oncology

MLN8054 and Alisertib (MLN8237): Discovery of Selective Oral Aurora A Inhibitors. (PubMed) - "Investigational agents MLN8054 (8) and alisertib (MLN8237, 10) have been identified as high affinity, selective, orally bioavailable inhibitors of Aurora A that have advanced into human clinical trials. Alisertib (10) is currently being evaluated in multiple Phase II and III clinical trials in hematological malignancies and solid tumors."

Journal • Biosimilar • Leukemia • Oncology

Aurora A inhibition disrupts chromosome condensation and spindle assembly during the first embryonic division in pigs. (PubMed, Reprod Domest Anim) - "Then, the potential role of Aurora A was further evaluated using a highly selective Aurora A inhibitor, MLN8054, during this mitotic progression in pig embryos. Further subcellular structure examination showed that Aurora A inhibition not only led to the failure of spindle microtubule assembly, but also resulted in severe defects in chromosome condensation, accompanied by an obvious decrease in p-TACC3(S558) expression during the prophase of the first mitosis. Together, these results illustrated that Aurora A is crucial for both spindle assembly and chromosome condensation during the first mitotic division in pig embryos, and that the regulation of Aurora A may be associated with its effects on p-TACC3(S558) expression."

Journal • TACC3

RIPK1-dependent cell death: a novel target of the Aurora kinase inhibitor Tozasertib (VX-680). (PubMed, Cell Death Dis) - "AT9283, AZD1152, Danusertib, MLN8054). The potency ranking of the newly derived Tozasertib analogues and their specificity profile, as observed in cellular assays, coincide with ADP-Glo recombinant kinase activity assays. Overall, we show that Tozasertib not only targets Aurora kinases but also RIPK1 independently, and that we could generate analogues with increased selectivity to RIPK1 or Aurora kinases, respectively."

Journal