Blog of Signaling Pathways

Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity

0 views | Sep 26 2023

CDK2 inhibitors in preclinical models reveal that acute inhibition of CDK2 leads to rapid loss of substrate phosphorylation, which is compensated by CDK4/6 activity to sustain cell cycle progression, suggesting that co-inhibition of CDK2 and CDK4/6 may be necessary for effective suppression of CDK2-driven cancers. [Read the Full Post]

HTLV-1 bZIP factor-induced reprogramming of lactate metabolism and epigenetic status promote leukemic cell expansion

80 views | Sep 26 2023

The study demonstrates that the viral oncogene HBZ upregulates TAp73, which in turn promotes lactate excretion through the upregulation of lactate transporters MCT1 and MCT4, revealing a potential common mechanism underlying cancer metabolism and suggesting the therapeutic potential of targeting this pathway. [Read the Full Post]

Mechanism of action of reserpine in producing gastric haemorrhage and erosion in the mouse

26 views | Sep 26 2023

Reserpine-like drugs, such as reserpine and deserpidine, induce gastric hemorrhage in mice within six hours of subcutaneous injection, likely through a mechanism involving central components and the release of 5-hydroxytryptamine. [Read the Full Post]

Monocarboxylate transporter 4 inhibition potentiates hepatocellular carcinoma immunotherapy through enhancing T cell infiltration and immune attack

19 views | Sep 26 2023

The study revealed that inhibiting MCT4 in hepatocellular carcinoma improved immune responses, suppressed tumor growth, and enhanced the efficacy of immunotherapy, suggesting MCT4 as a potential therapeutic target for tailoring HCC treatment. [Read the Full Post]

Post-Marketing Use of Teduglutide in a Large Cohort of Adults with Short Bowel Syndrome-Associated Chronic Intestinal Failure: Evolution and Outcomes

50 views | Sep 26 2023

This real-life study assessing teduglutide initiation and outcomes in SBS-CIF patients demonstrated its efficacy in reducing parenteral support volume and indicated a higher response rate in incident patients, suggesting a potential benefit in early treatment. [Read the Full Post]

An overview of PROTACs: a promising drug discovery paradigm

0 views | Sep 25 2023

This review provides a comprehensive analysis of the features of PROTAC technology, principles for designing efficient PROTACs, their applications across different protein categories, progress in clinical trials, and the challenges and limitations they may face, serving as a valuable reference for further advancements in PROTAC research and application. [Read the Full Post]

Estimation of Intangible Costs for Factors Associated with Oral Antiviral Drugs for COVID-19 Treatment: A Conjoint Analysis in Japan

0 views | Sep 25 2023

This study conducted a conjoint analysis to estimate the intangible costs of factors associated with oral antiviral drugs for COVID-19 among the Japanese population, revealing preferences regarding the company, formulation, size, frequency of administration, infectiousness duration, and out-of-pocket expenses. [Read the Full Post]

Upgrading nirmatrelvir to inhibit SARS-CoV-2 Mpro via DeepFrag and free energy calculations

23 views | Sep 25 2023

The hybrid approach combining machine learning and free energy simulations proposed six modified compounds derived from nirmatrelvir, which exhibited enhanced electrostatic interaction free energy with SARS-CoV-2 Mpro and potentially reduced toxicity compared to the original inhibitor. [Read the Full Post]

ZBTB7C m6A modification incurred by METTL3 aberration promotes osteosarcoma progression

23 views | Sep 25 2023

The study reveals that elevated METTL3 and increased m6A modification, particularly on ZBTB7C mRNA, play a crucial role in promoting osteosarcoma progression, suggesting that targeting the METTL3/ZBTB7C axis could be a potential therapeutic strategy. [Read the Full Post]

Targeting homologous recombination deficiency in uterine leiomyosarcoma

22 views | Sep 25 2023

This report highlights the significance of identifying homologous recombination deficiency in uterine leiomyosarcoma (uLMS) for therapeutic targeting with poly (ADP-ribose) polymerase (PARP) inhibitors and platinum agents, demonstrating encouraging clinical responses and suggesting the potential for PARP1-specific PARP inhibitors in future trials. [Read the Full Post]

The potent AMPK inhibitor BAY-3827 shows strong efficacy in androgen-dependent prostate cancer models

52 views | Sep 24 2023

The novel and potent AMPK inhibitor BAY-3827 demonstrates strong anti-proliferative effects in androgen-dependent prostate cancer cell lines, upregulates genes involved in lipid metabolism, and inhibits key components of the lipid flux pathway, providing valuable insights into the role of AMPK signaling in cancer, especially in prostate cancer. [Read the Full Post]

Synergistic apoptosis by combination of metformin and an O-GlcNAcylation inhibitor in colon cancer cells

18 views | Sep 24 2023

The combinatorial treatment of metformin and OSMI-1 synergistically induced apoptosis in colon cancer cells by enhancing ER stress-induced signaling and disrupting autophagy, as evidenced by in vitro and xenograft tumor experiments. [Read the Full Post]

A phase 1 study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of danuglipron (PF-06882961), an oral small-molecule glucagon-like peptide-1 receptor agonist, in Japanese adults with type 2 diabetes mellitus

27 views | Sep 24 2023

In Japanese participants with type 2 diabetes mellitus, the oral small-molecule glucagon-like peptide-1 receptor agonist danuglipron demonstrated dose-proportional increases in exposure, significantly reduced glycaemic parameters and body weight, and exhibited a safety profile consistent with its mechanism of action. [Read the Full Post]

Discovery of Novel 5,6-Dihydro-1,2,4-triazine Derivatives as Efficacious Glucagon-Like Peptide-1 Receptor Agonists

59 views | Sep 24 2023

The study introduces compound 42, a novel 5,6-dihydro-1,2,4-triazine derivative, as a highly potent and selective GLP-1R agonist with improved efficacy, selectivity, and duration of action compared to danuglipron, demonstrating its potential for the treatment of type 2 diabetes mellitus and obesity. [Read the Full Post]

Discovery and resistance mechanism of a selective CDK12 degrader

47 views | Sep 24 2023

The study presents the development of a CDK12-specific degrader, BSJ-4-116, which selectively degrades CDK12, resulting in premature cleavage and poly(adenylation) of DNA-damage response genes, and exhibits potent antiproliferative effects alone and in combination with olaparib, but resistance mutations in CDK12 were identified as potential mechanisms for tumor cells to evade the degrader. [Read the Full Post]

Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology-College of American Pathologists Guideline Update

27 views | Sep 23 2023

The American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) affirms the 2018 recommendations for HER2 testing in breast cancer but highlights the importance of distinguishing between immunohistochemistry (IHC) 0 and 1+ results and provides best practice recommendations for this distinction. [Read the Full Post]

Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial

63 views | Sep 23 2023

The MMPOWER-3 trial evaluating the efficacy of elamipretide in individuals with Primary Mitochondrial Myopathies did not show significant improvements in physical function and fatigue but established the drug's safety and tolerability. [Read the Full Post]

Identifying responders to elamipretide in Barth syndrome: Hierarchical clustering for time series data

38 views | Sep 23 2023

This proof-of-concept study demonstrated that wearable device data can predict functional status and response to elamipretide treatment in patients with Barth syndrome (BTHS). [Read the Full Post]

Pathway network of pyroptosis and its potential inhibitors in acute kidney injury

67 views | Sep 23 2023

This article reviews the role of pyroptosis in acute kidney injury (AKI), focusing on the assembly and activation of the NLRP3 inflammasome and its downstream inflammatory cytokines as potential therapeutic targets for novel AKI therapies. [Read the Full Post]

Precious Gene: The Application of RET-Altered Inhibitors

115 views | Sep 23 2023

The novel RET-specific inhibitors selpercatinib and pralsetinib, along with ongoing clinical trials of TPX-0046 and zetletinib, demonstrate promising efficacy and safety in the treatment of RET-altered cancers, addressing the limitations of previous multikinase inhibitors. [Read the Full Post]