Blog of Signaling Pathways

Nedd8-Activating Enzyme Is a Druggable Host Dependency Factor of Human and Mouse Cytomegalovirus

109 views | Sep 02 2023

The study suggests that the Nedd8-activating enzyme (NAE), the neddylation process, and cullin RING ubiquitin ligases (CRLs) are potential targets for developing drugs against cytomegalovirus infections. [Read the Full Post]

REV1 promotes lung tumorigenesis by activating the Rad18/SERTAD2 axis

77 views | Sep 02 2023

The study suggests that REV1 is a potential diagnostic marker and therapeutic target for lung cancer, and the novel REV1 inhibitor, JH-RE-06, shows promise as a safe and efficient therapeutic agent for NSCLC. [Read the Full Post]

Real-world outcomes and direct care cost before and after elexacaftor/tezacaftor/ivacaftor initiation in commercially insured members with cystic fibrosis

25 views | Sep 02 2023

The study found that among commercially insured individuals with cystic fibrosis initiating treatment with ELX/TEZ/IVA, there was a significant increase in total cost of care, primarily driven by increased pharmacy benefit costs, despite notable reductions in healthcare resource utilization and pulmonary exacerbation events. [Read the Full Post]

Positive and negative impacts of elexacaftor/tezacaftor/ivacaftor: Healthcare providers' observations across US centers

32 views | Sep 02 2023

This study found that while Elexacaftor/tezacaftor/ivacaftor (ETI) had positive physical effects in cystic fibrosis patients, it was also associated with negative side effects such as sleep difficulties and worsening psychological functioning. [Read the Full Post]

Analysis of the ERK Pathway Cysteinome for Targeted Covalent Inhibition of RAF and MEK Kinases

63 views | Sep 02 2023

This study presents a systematic analysis of the covalent ligandabilities of ERK pathway kinases, identifying reactive cysteine residues and proposing potential scaffolds for the design of novel covalent inhibitors, thereby providing valuable insights for the development of targeted therapies against tumorigenesis. [Read the Full Post]

Safety and Efficacy of Baseline Antiplatelet Treatment in Patients Undergoing Mechanical Thrombectomy for Ischemic Stroke

22 views | Sep 01 2023

In this nationwide study, baseline antiplatelet treatment prior to mechanical thrombectomy for acute ischemic stroke did not improve functional independence or increase the risk of intracranial hemorrhage. [Read the Full Post]

Synthesis, Characterization, Antimicrobial Properties, and Antioxidant Activities of Silver-N-Heterocyclic Carbene Complexes

16 views | Sep 01 2023

The study describes the synthesis and characterization of silver-NHC complexes, which exhibit strong antibacterial activity and significant antioxidant properties, offering potential as effective and multifunctional antimicrobial agents. [Read the Full Post]

De novo pyrimidine synthesis is a targetable vulnerability in IDH mutant glioma

69 views | Sep 01 2023

The discovery of the hypersensitivity of IDH1-mutant glioma cells to DHODH inhibitors presents a promising, biomarker-guided therapeutic strategy for the treatment of aggressive glioma. [Read the Full Post]

Investigating dihydroorotate dehydrogenase inhibitor mediated mitochondrial dysfunction in hepatic in vitro models

60 views | Sep 01 2023

The study found that while DHODH inhibitors showed multifactorial toxicity and moderate indications of respiratory chain dysfunction or uncoupling in HepaRG® cells, leflunomide and brequinar specifically exhibited mitochondrial toxicity in HepG2 cells, indicating a potential role of biotransformation in mediating or masking hepatic mitochondrial liabilities. [Read the Full Post]

Evaluation of the Cytochrome P450 3A and P-glycoprotein Drug-Drug Interaction Potential of Futibatinib

23 views | Sep 01 2023

Futibatinib, an FGFR1-4 inhibitor, should not be concomitantly used with dual P-gp and strong CYP3A inhibitors/inducers but can be administered alongside other drugs metabolized by CYP3A, as demonstrated in phase I studies. [Read the Full Post]

m6A demethylase FTO renders radioresistance of nasopharyngeal carcinoma via promoting OTUB1-mediated anti-ferroptosis

35 views | Aug 31 2023

The upregulation of the m6A mRNA demethylase FTO in radioresistant nasopharyngeal carcinoma (NPC) promotes radiotherapy resistance by inhibiting radiation-induced ferroptosis, suggesting FTO as a potential therapeutic target and prognostic biomarker for NPC. [Read the Full Post]

Development of Highly Potent and Selective Pyrazolopyridine Inhibitor of CDK8/19

0 views | Aug 31 2023

JH-XVI-178 (compound 15) is a highly potent and selective inhibitor of CDK8/19, overcoming metabolic challenges and displaying favorable pharmacokinetic properties. [Read the Full Post]

SEL120-34A is a novel CDK8 inhibitor active in AML cells with high levels of serine phosphorylation of STAT1 and STAT5 transactivation domains

26 views | Aug 31 2023

SEL120-34A, a substituted tricyclic benzimidazole and inhibitor of Cyclin-dependent kinase 8 (CDK8), shows promise as a personalized therapeutic approach in acute myeloid leukemia (AML) by targeting oncogenic transcriptional programs through inhibition of STAT5 phosphorylation. [Read the Full Post]

Chemical inhibition of DNA-PKcs impairs the activation and cytotoxicity of CD4+ helper and CD8+ effector T cells

97 views | Aug 31 2023

Inhibition of DNA-PKcs using small-molecule inhibitors abrogates T cell activation, impairs metabolic pathways and proliferation, and reduces cytotoxicity, highlighting its potential as a therapeutic target for immune modulation in autoimmune diseases, immune-related disorders, and cancer. [Read the Full Post]

Identification of a Cryptic Binding Site in CRISPR-Cas9 for Targeted Inhibition

55 views | Aug 31 2023

This study discovered a hidden ligand binding site within the carboxyl-terminal domain (CTD) of CRISPR-Cas9, revealing how the binding of small molecules induces structural changes that inhibit the function of Cas9. [Read the Full Post]

Targeting KRAS in pancreatic cancer: Emerging therapeutic strategies

78 views | Aug 30 2023

This chapter provides an overview of KRAS biochemistry, signaling pathways, different mutations, emerging KRAS-targeted therapies, combination strategies, challenges in KRAS targeting, and future directions with a specific emphasis on pancreatic cancer. [Read the Full Post]

Clinical Characterization of Targetable Mutations (BRAF V600E and KRAS G12C) in Advanced Colorectal Cancer-A Nation-Wide Study

101 views | Aug 30 2023

The retrospective analysis revealed that BRAF V600E mutation in metastatic colorectal cancer is associated with factors such as female sex, right colon primary location, and specific histological features, while KRAS G12C mutation is linked to left colon primary tumors and brain metastases, suggesting potential therapeutic targets and the need for further investigation. [Read the Full Post]

Evaluation of KRASG12C inhibitor responses in novel murine KRASG12C lung cancer cell line models

68 views | Aug 30 2023

The generation of three novel murine KRASG12C-driven lung cancer cell lines provides valuable models for studying and improving therapeutic combination strategies with KRASG12C inhibitors. [Read the Full Post]

Design of rigid protein-protein interaction inhibitors enables targeting of undruggable Mcl-1

32 views | Aug 30 2023

This work demonstrates the successful design of highly rigid inhibitors that induce a deepening of the protein binding pocket, providing valuable insights for targeting protein-protein interactions (PPIs) and potentially enabling the development of therapies for hematological cancers. [Read the Full Post]

Synergism of BCL-2 family inhibitors facilitates selective elimination of senescent cells

64 views | Aug 30 2023

This study investigates the synergistic effects of combining BCL-2 family inhibitors, particularly BH3 mimetics, to eliminate senescent cells and overcome resistance within the population, potentially providing a more effective and less toxic approach to treating age-associated diseases. [Read the Full Post]