SNS-314 / Viracta Therap - LARVOL DELTA

Evaluation of anti-leukemic activity of symmetrical 5-aminopyrazolyl disulfide derivatives. (PubMed, Bioorg Chem) - "Further Western blot analyses of Hsp70 and Hsp90α expression, together with molecular simulation studies, revealed that compounds 4a exhibited favorable inhibitory profiles, including optimal structural alignment, suitable molecular interactions, and higher total interaction energies, comparable to the clinical agent SNS-314 and superior to the reference compound DADS. Based on these findings, compound 4a emerge as promising lead candidates for further development as potential antileukemic agents."

Journal • Hematological Malignancies • Leukemia • Oncology • CDC37 • HSP90AA1

Rational Inhibitor Discovery for BRAFV600E Using PSeMut, a Sequence-Driven Model. (PubMed, FASEB J) - "In the selected validation assays, SNS-314 showed mutation-selective cellular activity (IC50 = 0.45 μM in BRAFV600E; 7.5-fold vs. BRAFWT), suppressed the BRAF-MEK-ERK signaling axis, and produced about 50% tumor growth inhibition in vivo without overt toxicity. Together, these results validate the effectiveness of PSeMut in a structure-free, mutation-aware screening workflow that links sequence-driven modeling to experimental confirmation and enables rational prioritization of mutation-resilient scaffolds across heterogeneous disease settings."

Journal • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • BRAF

Exploring the utility of zinc finger protein-related genes in predicting hepatocellular carcinoma prognosis, immune responses, and drug efficacy. (PubMed, Hum Exp Toxicol) - "The low-risk group exhibited enhanced immune cell infiltration, contrasting with cell cycle and DNA replication enrichment in the high-risk group, which also displayed increased mutation rates. Promising drug candidates like SNS-314 and Decitabine warrant further investigation in LIHC treatment.ConclusionThis study introduces impactful prognostic markers for LIHC management, emphasizing the significance of ZNFs in predicting patient outcomes and guiding treatment strategies."

Biomarker • Journal • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor

Screen of the ReFRAME Compound Library for Therapeutic Agents to Prevent Red Blood Cell Sickling Using an Improved High Throughput Sickling Assay. (PubMed, ACS Omega) - "We were able to increase the number of blood samples that were adequate for identifying anti-sickling compounds in the improved sickling assay and identified voxelotor and SNS-314 as compounds that successfully prevented sickling. The improved sickling assay will increase access to valuable blood samples from SCD volunteers, providing more opportunities to develop anti-sickling compounds for treating SCD."

Journal • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Thienopyrimidine: A promising scaffold in the development of kinase inhibitors with anticancer activities. (PubMed, Bioorg Med Chem) - "Some of these thienopyrimidines as anticancer kinase inhibitors have already been marketed or are currently undergoing clinical/preclinical studies for the treatment of cancers, such as Olmutinib, Pictilisib, SNS-314, PF-03758309, and Fimepinostat, highlighting the substantial advantages of the thienopyrimidine scaffold in the discovery of anticancer agents. This article reviews the discovery, activity, and structure-activity relationships of antitumor kinase inhibitors based on the thienopyrimidine scaffold, and partially discusses the binding modes between thienopyrimidine derivatives and their kinase targets. By elucidating the application of thienopyrimidine derivatives as anticancer kinase inhibitors, this review aims to provide new perspectives for the development of more effective and novel kinase inhibitors."

Journal • Review • Oncology

Synthesis, design, and antiproliferative evaluation of 6-(N-Substituted-methyl)pyrazolo[3,4-d]pyrimidines as the potent anti-leukemia agents. (PubMed, Bioorg Chem) - "On the other hand, further SAR inhibition and docking model studies revealed that compound 19d, which has a 3-(1H-imidazol-1-yl)propan-1-amino side-chain on the C-6 position, was able to form four hydrogen bonds with residues Ala226, Leu152, and Glu194 and specifically extended into the P1 pocket subsite with Aurora A, resulting in improved inhibitory activity almost similar to SNS-314. Through further comparisons of the model superposition of three-dimensional (3D) conformations in DHFR, compound 19d presented a similar structural alignment to Methotrexate and the reported naphthalene derivative and led to similar drug-like functional relationships. As a results, compound 19d would be a potential DHFR inhibitor for anti-leukemia drug candidate."

Journal • Hematological Malignancies • Leukemia • Oncology • DHFR

The metabolic mechanisms of Cd-induced hormesis in photosynthetic microalgae, Chromochloris zofingiensis. (PubMed, Sci Total Environ) - "Notably, Aurora A kinases consistently displayed varying expression levels across all Cd treatments, and their role in microalgal hormesis was confirmed through validation with SNS-314 mesylate. This study unveils the intricate regulatory mechanisms of Cd-induced hormesis in C. zofingiensis, with implications for environmental remediation and industrial microalgae applications."

Journal • AURKA • CAT

Stretch Induced Activation of Hippo Signaling in Lung Microvascular Endothelial Cells, a Novel Mechanism of Overventilation Induced Pulmonary Fibrosis (ATS 2022) - "Probing the role of potential mechanosensitive signaling pathways, we found that stretch-induced TAZ translocation was mitigated by the pharmacological inhibition of Aurora kinase and FAK using SNS 314 mesylate or FAK 14, respectively... Our data suggest that mechanical stretch activates TAZ nuclear translocation via a Aurora kinase- and FAK dependent manner. Knocking down TAZ in endothelial cells protected mice from developing pulmonary fibrosis following HCl challenge and subsequent overventilation. Interventions targeted at the Hippo-signaling pathway may present potential strategies to counteract the detrimental effects of mechanical overventilation."

Acute Respiratory Distress Syndrome • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • AURKA • RHOA

High-Throughput Assay to Screen Small Molecules for Their Ability to Prevent Sickling of Red Blood Cells. (PubMed, ACS Omega) - "SNS-314 mesylate prevented sickling in the absence of oxygen, while voxelotor did not, suggesting that SNS-314 mesylate acts by a mechanism that is different from that of voxelotor. The sickling assay described in this study will permit the identification of additional, novel antisickling compounds, which will potentially expand the therapeutic options for SCD."

Journal • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Epigenome-wide DNA methylation analysis of small cell lung cancer cell lines suggests potential chemotherapy targets. (PubMed, Clin Epigenetics) - "Multiple associations indicate potential epigenetic mechanisms affecting SCLC response to chemotherapy and suggest targets for combination therapies. While many correlations were not specific to SCLC lineages, several lineage markers were associated with specific agents."

IO Biomarker • Journal • Preclinical • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • Thoracic Cancer • ATR • EPAS1 • EPHA2 • EZH2 • SLFN11 • STING • YAP1

A New Quantitative Cell-Based Assay Reveals Unexpected Microtubule Stabilizing Activity of Certain Kinase Inhibitors, Clinically Approved or in the Process of Approval. (PubMed, Front Pharmacol) - "Using this assay to screen a kinase inhibitor library allowed the selection of seven known kinase inhibitors: selonsertib, masatinib, intedanib, PF0477736, SNS-314 mesylate, MPI0479605, and ponatinib. Their microtubule-stabilizing effect may account for their therapeutic effect as well as for some of their adverse side effects. These results indicate also a possible repurposing of some of these drugs."

Clinical • Journal • Oncology

Associations of epigenome-wide DNA methylation patterns with chemosensitivity and chemoresistance of small cell lung cancer cell lines (AACR-NCI-EORTC 2019) - "Increased methylation and low expression of TREX1 were associated with SCLC cell line sensitivity to multiple Aurora kinase inhibitors AZD-1152, SCH-1473759, SNS-314, and TAK-901, as well as to the CDK inhibitor R-547, Vertex ATR inhibitor Cpd 45, and the mitotic spindle disruptor vinorelbine...Among other examples, EPAS1 (HIF2A) was associated with several Aurora kinase inhibitors, the PLK1 inhibitor GSK-461364, and the Bcl-2 inhibitor ABT-737...IGFBP5, which is expressed in the tuft cell-like SCLC subtype, was associated with the mTOR inhibitor INK-128...Methylation and expression of YAP1, a SCLC lineage driver regulating the Hippo pathway, were correlated with the MTOR inhibitor rapamycin...The 5’ UTR region of the epigenetic modifier EZH2 was associated with Aurora kinase inhibitors and the FGFR inhibitor BGJ-398. These and multiple other associations identified in this study provide a novel understanding of epigenetic mechanisms which may modulate SCLC response to..."

IO Biomarker • Preclinical • EPAS1 • EPHA2 • EZH2