Blog of Signaling Pathways

Effects of arsenic on the topology and solubility of promyelocytic leukemia (PML)-nuclear bodies

50 views | Aug 21 2023

Trivalent arsenic (As3+) induces a solubility shift in PML, leading to rapid SUMOylation and late agglomeration of PML nuclear bodies (PML-NBs), which has implications for the regulation of intranuclear dynamics in the context of acute promyelocytic leukemia (APL). [Read the Full Post]

Results of an open-label phase 1b study of the ERK inhibitor MK-8353 plus the MEK inhibitor selumetinib in patients with advanced or metastatic solid tumors

33 views | Aug 21 2023

The combination of MK-8353 and selumetinib at 50/25 mg and 100/50 mg doses demonstrated acceptable safety and tolerability in patients with advanced solid tumors, while the 150/75 mg dose level was found to be intolerable with no observed objective responses. [Read the Full Post]

Pro-inflammatory role of Wnt/β-catenin signaling in endothelial dysfunction

122 views | Aug 21 2023

The inhibition of the Wnt/β-catenin signaling pathway with iCRT-14 improved endothelial function by reducing inflammation and monocyte adhesion but also exhibited pro-coagulatory effects and hindered wound healing, which may impact its suitability as a therapy for atherosclerosis and vein graft failure. [Read the Full Post]

Molecular basis and targeted therapy in thyroid cancer: Progress and opportunities

72 views | Aug 21 2023

Thyroid cancer management has advanced with the development of targeted therapies, such as multi-tyrosine kinase inhibitors and immune checkpoint inhibitors, offering potential options for controlling tumor progression and addressing resistance mechanisms. [Read the Full Post]

Selective Inhibition of L-type Amino Acid Transporter 1 Suppresses Cell Proliferation in Ovarian Clear Cell Carcinoma

23 views | Aug 20 2023

Selective inhibition of L-type amino acid transporter 1 (LAT1) using nanvuranlat (JPH203) effectively suppresses cell proliferation via the mTOR pathway by inhibiting leucine uptake in ovarian clear cell carcinoma (OCCC), suggesting LAT1 as a potential therapeutic target for this aggressive ovarian cancer. [Read the Full Post]

Discovery of GDC-0077 (Inavolisib), a Highly Selective Inhibitor and Degrader of Mutant PI3Kα

30 views | Aug 20 2023

Researchers have developed a series of benzoxazepin-oxazolidinone ATP-competitive inhibitors, including GDC-0077 (inavolisib), which selectively target and degrade mutant p110α protein, a catalytic subunit of PI3Kα, demonstrating potential for the treatment of PIK3CA-mutant breast cancer in a Phase III clinical trial. [Read the Full Post]

MUC1-C is a master regulator of MICA/B NKG2D ligand and exosome secretion in human cancer cells

17 views | Aug 20 2023

Targeting the MUC1-C protein in cancer cells enhances the expression of MICA/B ligands, inhibits their cleavage, reduces exosome secretion, and promotes NK cell-mediated killing, uncovering mechanisms by which MUC1-C confers immune evasion to cancer cells. [Read the Full Post]

Preclinical Evaluation of SCC244 (Glumetinib), a Novel, Potent, and Highly Selective Inhibitor of c-Met in MET-dependent Cancer Models

89 views | Aug 20 2023

SCC244, a novel and highly selective inhibitor of c-Met kinase, demonstrated potent antitumor activity in preclinical studies, inhibiting c-Met signaling and suppressing neoplastic phenotypes in tumor and endothelial cells, suggesting its potential as a therapeutic agent for tumors with c-Met pathway alterations. [Read the Full Post]

CXCR3 antagonist AMG487 ameliorates experimental autoimmune prostatitis by diminishing Th1 cell differentiation and inhibiting macrophage M1 phenotypic activation

42 views | Aug 20 2023

The study demonstrates that treatment with the CXCR3 antagonist AMG487 can effectively alleviate inflammation and pelvic pain in a mouse model of experimental autoimmune prostatitis (EAP), suggesting its potential as a therapeutic agent for the prevention and treatment of chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS). [Read the Full Post]

Transforming growth factor-β-activated kinase 1 (TAK1) mediates chronic pain and cytokine production in mouse models of inflammatory, neuropathic, and primary pain

48 views | Aug 19 2023

The study demonstrated that inhibiting TAK1 with the small molecule inhibitor takinib alleviated pain and inflammation in various models of chronic pain, indicating its potential as a novel drug target for the treatment of different types of chronic pain syndromes. [Read the Full Post]

Development and Efficacy of an Orally Bioavailable Selective TAK1 Inhibitor for the Treatment of Inflammatory Arthritis

81 views | Aug 19 2023

HS-276, a potent and selective orally bioavailable TAK1 inhibitor, shows promise in inhibiting TNF-mediated cytokine profiles and attenuating arthritic-like symptoms in a mouse model of inflammatory rheumatoid arthritis, suggesting it as a potential alternative to current biologic-based therapies. [Read the Full Post]

Combined Targeting of the BRD4-NUT-p300 Axis in NUT Midline Carcinoma by Dual Selective Bromodomain Inhibitor, NEO2734

76 views | Aug 19 2023

Combining selective p300/CBP and BET bromodomain inhibitors demonstrates potent inhibition of NMC growth, induction of cell differentiation, and improved survival in xenograft models, providing a strong rationale for clinical study of the dual inhibitor NEO2734 in patients with NMC. [Read the Full Post]

Preclinical validation of a novel therapeutic strategy for choroid plexus carcinoma

104 views | Aug 19 2023

This study represents a pioneering effort in identifying promising combinatorial therapeutics and highlighting the potential of intra-arterial delivery for the treatment of choroid plexus carcinoma, a rare and aggressive brain tumor in children. [Read the Full Post]

Nuclear pCHK1 as a potential biomarker of increased sensitivity to ATR inhibition

54 views | Aug 19 2023

The study suggests that the nuclear-specific enrichment of checkpoint kinase 1 (CHK1) and higher levels of nuclear phosphorylated CHK1 (pCHK1) staining may serve as potential predictive biomarkers for sensitivity to the ATR inhibitor elimusertib in cancer cells. [Read the Full Post]

[Fuyu Decoction improves ventricular remodeling in rats with heart failure by inhibiting AMPK/mTOR pathway-mediated autophagy]

26 views | Aug 18 2023

Fuyu Decoction improves ventricular remodeling in rats with heart failure by inhibiting AMPK/mTOR signaling-mediated autophagy in cardiomyocytes. [Read the Full Post]

Development and clinical application of a liquid chromatography-tandem mass spectrometry-based assay to quantify eight tyrosine kinase inhibitors in human plasma

28 views | Aug 18 2023

This study successfully developed and validated a sensitive LC-MS/MS assay for the quantification of eight tyrosine kinase inhibitors in human plasma, demonstrating its potential clinical utility in therapeutic drug monitoring. [Read the Full Post]

Metastatic effects of environmental carcinogens mediated by MAPK and UPR pathways with an in vivo Drosophila Model

30 views | Aug 18 2023

This study revealed that exposure to environmental carcinogens (PCB126, PFOA, and CdCl2) increased tumor invasion rates, disrupted larval body weight and locomotion behavior, and influenced the expression of genes in the MAPK and UPR pathways, with the sna/E-cad pathway playing a crucial role in connecting the effects of these carcinogens on UPR and MAPK regulations and the resultant metastasis. [Read the Full Post]

ADAM10 mediates shedding of carbonic anhydrase IX ectodomain non‑redundantly to ADAM17

22 views | Aug 18 2023

The study demonstrates that ADAM10, in addition to ADAM17, is capable of shedding the extracellular domain of Carbonic Anhydrase IX (CA IX), contributing to tumor adaptation, metastasis, and other functional aspects of CA IX in cancer cells. [Read the Full Post]

β-catenin ameliorates myocardial infarction by preventing YAP-associated apoptosis

82 views | Aug 18 2023

The study demonstrated that upregulation of β-catenin in myocardial infarction (MI) reduces cardiac tissue damage and cardiomyocyte apoptosis, and this effect is mediated, at least in part, through the reactivation of Yes-Associated Protein (YAP). [Read the Full Post]

[Roles of the CXCR1/CXCL8 axis in abnormal proliferation of bile duct epithelial cells in primary biliary cholangitis]

69 views | Aug 17 2023

The study concludes that the CXCR1/CXCL8 axis plays a role in the abnormal proliferation of bile duct epithelial cells in primary biliary cholangitis (PBC) through the activation of NF-κB and ERK pathways. [Read the Full Post]