Heat shock factor 1 (HSF1) is a transcription factor that plays key roles in cancer, including providing a mechanism for cell survival under proteotoxic stress. Therefore, inhibition of the HSF1-stress pathway represents an exciting new opportunity in cancer treatment. We employed an unbiased phenotypic screen to discover inhibitors of the HSF1-stress pathway. Using this approach we identified an initial hit () based on a 4,6-pyrimidine scaffold (2.00 μM). Optimisation of cellular SAR led to an inhibitor with improved potency (, 15 nM) in the HSF1 phenotypic assay. The 4,6-pyrimidine was also shown to have high potency against the CDK9 enzyme (3 nM).
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http://dx.doi.org/10.1039/c6md00159a | DOI Listing |
FASEB J
January 2025
Prostate Cancer/Genitourologic Program, Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Among the known nuclear exportins, CRM1 is the most studied prototype. Dysregulation of CRM1 occurs in many cancers, hence, understanding the role of CRM1 in cancer can help in developing synergistic therapeutics. The study investigates how CRM1 affects prostate cancer growth and survival.
View Article and Find Full Text PDFCell Biol Toxicol
January 2025
Department of Oral Anatomy and Physiology, Hospital of Stomatology, Jilin Provincial Key Laboratory of Oral Biomedical Engineering, Jilin University, Changchun, 130021, China.
Novel strategies to disrupt tumor progression have emerged from studying the interactions between tumor cells and tumor-associated macrophages (TAMs). However, the molecular mechanisms of interactions between tumor cells and TAMs underlying oral squamous cell carcinoma (OSCC) progression have not been fully elucidated. This study explored the molecular mechanism of the HSP27/IL-6 axis in OSCC chemoresistance, invasion, and migration.
View Article and Find Full Text PDFLife Metab
October 2024
Key Laboratory of Agriculture Animal Genetics, Breeding and Reproduction of the Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
Obesity is considered an epidemic often accompanied by insulin resistance (IR). Heat treatment (HT) has been shown to prevent high-fat diet-induced IR in skeletal muscle, but the underlying mechanisms are poorly understood. In this study, we discovered that high temperature alleviated the hallmarks of obesity by promoting glycogen synthesis and lowering blood glucose levels in skeletal muscle tissue (SMT).
View Article and Find Full Text PDFCurr Protein Pept Sci
January 2025
Department of Pharmacy, Panipat Institute of Engineering and Technology, India.
The three-dimensional structure of proteins, achieved through the folding of the nascent polypeptide chain in vivo, is largely facilitated by molecular chaperones, which are crucial for determining protein functionality. In addition to aiding in the folding process, chaperones target misfolded proteins for degradation, acting as a quality control system within the cell. Defective protein folding has been implicated in a wide range of clinical conditions, including neurodegenerative and metabolic disorders.
View Article and Find Full Text PDFMicrosc Res Tech
January 2025
Department of Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt.
Arrhythmia is a common and serious global health problem, contributing to cardiovascular morbidity and mortality. The cardiac muscle is susceptible to ischemia-reperfusion (I/R) injury, which can lead to fatal arrhythmias during open-heart surgery. We investigated the potential prophylactic effect of angiotensin 1-7 (Ang 1-7) using an in vivo rat model of I/R injury and examined the underlying mechanisms.
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