A5001498030- Cancer, Hypoxia, and Metabolism
- Cancer-related Molecular Pathways
- Hemoglobin structure and function
- Pharmacological Receptor Mechanisms and Effects
- Cancer Genomics and Diagnostics
- ATP Synthase and ATPases Research
- Cytokine Signaling Pathways and Interactions
- Cell Adhesion Molecules Research
- Heme Oxygenase-1 and Carbon Monoxide
- Melanoma and MAPK Pathways
- Virus-based gene therapy research
- Neuroblastoma Research and Treatments
- Coordination Chemistry and Organometallics
- Mast cells and histamine
- Cutaneous Melanoma Detection and Management
- interferon and immune responses
- Chronic Lymphocytic Leukemia Research
- Protein Degradation and Inhibitors
- Lymphoma Diagnosis and Treatment
- Ovarian cancer diagnosis and treatment
- Microtubule and mitosis dynamics
- Chemical synthesis and alkaloids
- RNA modifications and cancer
- Lung Cancer Research Studies
- Phosphodiesterase function and regulation
Inhibition of oncogenic transcriptional programs is a promising therapeutic strategy. A substituted tricyclic benzimidazole, SEL120-34A, novel inhibitor Cyclin-dependent kinase 8 (CDK8), which regulates transcription by associating with the Mediator complex. X-ray crystallography has shown SEL120-34A to be type I forming halogen bonds protein's hinge region and hydrophobic complementarities within its front pocket. inhibits phosphorylation STAT1 S727 STAT5 S726 in cancer cells vitro....
Melanoma can be stratified into unique subtypes based on distinct pathologies. The acral/mucosal melanoma subtype is characterized by aberrant and constitutive activation of the proto-oncogene receptor tyrosine kinase C-KIT, which drives tumorigenesis. Treatment these patients with C-KIT inhibitors has proven challenging, prompting us to investigate downstream effectors receptor. We determined that stimulates MAP kinase-interacting serine/threonine kinases 1 2 (MNK1/2), phosphorylate...
Abstract Energy and biomass production in cancer cells are largely supported by aerobic glycolysis what is called the Warburg effect. The process regulated key enzymes, among which phosphofructokinase PFK‐2 plays a significant role producing fructose‐2,6‐biphosphate; most potent activator of rate‐limiting step performed PFK‐1. Herein, synthesis, biological evaluation structure–activity relationship novel inhibitors 6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase 3 (PFKFB3), ubiquitous...
Due to increased lactate production during glucose metabolism, tumor cells heavily rely on efficient transport avoid intracellular accumulation and acidification. Monocarboxylate transporter 4 (MCT4/SLC16A3) is a that plays central role in pH modulation. The discovery optimization of novel class MCT4 inhibitors (hit 9a), identified by cellular screening MDA-MB-231, described. Direct target interaction the optimized compound 18n with cytosolic domain was shown after solubilization GFP-tagged...
Elevated expression of heme oxygenase-1 (HO-1, encoded by HMOX1) is observed in various types tumors. Hence, it suggested that HO-1 may serve as a potential target anticancer therapies. A novel approach to inhibit related the synthetic lethality this enzyme and fumarate hydratase (FH). In current study, we aimed validate effect genetic pharmacological inhibition cells isolated from patients suffering hereditary leiomyomatosis renal cell carcinoma (HLRCC)-an inherited cancer syndrome, caused...
Abstract The synthetic lethality resulting from the inhibition of WRN helicase protein has been observed in tumors characterized by high levels microsatellite instability (MSI-H). This stems a deficiency DNA mismatch repair (MMR) mechanisms, leading to accumulation damage. phenomenon is notably prevalent 10-30% colorectal, gastric, endometrial, and ovarian cancers. Specifically, activity induces damage cell cycle arrest apoptosis exclusively MSI-H lines. selectivity underscores therapeutic...
Abstract GCN2 is a protein kinase capable of sensing amino acid (AA) shortage. It gets activated by binding unloaded tRNAs and subsequently phosphorylates translation initiation factor 2 alpha (eIF2α) eventually leading to induction ATF4-mediated integrated stress response (ISR). Elevated catabolism one the essential acids - tryptophan (Trp), driven overexpression critical enzymes in Trp metabolism IDO TDO, leads immunosuppressive microenvironment many types cancer. key effector signaling...
Abstract Cyclin-dependent kinase 8 inhibitors (CDK8i) have anti-cancer activity in human acute myeloid leukaemia (AML) cell lines both vitro and vivo. Activity of CDK8i often involves deregulation super-enhancer-associated genes AML lines. Previous studies established SEL120 as a specific CDK8 inhibitor active cells with increased STAT1/5 signalling pathways. Differential gene expression analysis demonstrated high enrichment stem (LSC) signatures responding cells, linked to resistance...
In this study, we present the discovery and pharmacological characterization of a new series 6-piperazinyl-7-azaindoles. These compounds demonstrate potent antagonism selectivity against 5-HT6 receptor. Our research primarily focuses on optimizing lead structure investigating structure-activity relationship (SAR) these compounds. objective is to improve their physicochemical properties, ADME (absorption, distribution, metabolism, excretion) off-target receptors.Overall, our findings...