AI Article Synopsis
- * A previous study detailed Astex's method for screening compounds against Hsp90 and finding two effective "hits."
- * This paper discusses how scientists optimized one lead molecule, 2,4-dihydroxybenzamide, and the strategies used to develop AT13387, which is now in clinical testing.
Article Abstract
Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) are currently generating significant interest in clinical development as potential treatments for cancer. In a preceding publication (DOI: 10.1021/jm100059d ) we describe Astex's approach to screening fragments against Hsp90 and the subsequent optimization of two hits into leads with inhibitory activities in the low nanomolar range. This paper describes the structure guided optimization of the 2,4-dihydroxybenzamide lead molecule 1 and details some of the drug discovery strategies employed in the identification of AT13387 (35), which has progressed through preclinical development and is currently being tested in man.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/jm100060b | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Heat shock protein A1A (HSPA1A) is a molecular chaperone crucial in cell survival. In addition to its cytosolic functions, HSPA1A translocates to heat-shocked and cancer cells' plasma membrane (PM). In cancer, PM-localized HSPA1A (mHSPA1A) is associated with increased tumor aggressiveness and therapeutic resistance, suggesting that preventing its membrane localization could have therapeutic value.
View Article and Find Full Text PDFGOLPH3-STIP1 Complex Activates STAT3 Through Exosome Secretion to Induce Colon Cancer Metastasis.
Biotechnol J
December 2024
Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
With a high mortality rate, colon cancer (CC) is the third most common malignant tumor worldwide. The primary causes are thought to be the high invasiveness and migration of CC cells. The functions of Golgi phosphoprotein 3 (GOLPH3), stress-induced phosphoprotein 1 (STIP1), and the signal transducer and activator of transcription 3 (STAT3) signaling pathway in the invasion and migration of CC cells were examined in this study.
View Article and Find Full Text PDFThe N-degron pathway mediates the autophagic degradation of cytosolic mitochondrial DNA during sterile innate immune responses.
Cell Rep
December 2024
Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea; Convergence Research Center for Dementia, Seoul National University Medical Research Center, Seoul 110-799, Republic of Korea; AUTOTAC Bio, Inc., Changkkyunggung-ro 254, Jongno-gu, Seoul 03077, Republic of Korea; Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea. Electronic address:
The human body reacts to tissue damage by generating damage-associated molecular patterns (DAMPs) that activate sterile immune responses. To date, little is known about how DAMPs are removed to avoid excessive immune responses. Here, we show that proteasomal dysfunction induces the release of mitochondrial DNA (mtDNA) as a DAMP that activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway and is subsequently degraded through the N-degron pathway.
View Article and Find Full Text PDFHSP60 controls mitochondrial ATP generation for optimal virus-specific IL-21-producing CD4 and cytotoxic CD8 memory T cell responses.
Commun Biol
December 2024
Institut national de la recherche scientifique (INRS)-Centre Armand-Frappier Santé Biotechnologie, 531 boulevard des Prairies, H7V 1M7, Laval, QC, Canada.
We have shown that virus-specific CD4 and CD8 memory T cells (TM) induce autophagy after T cell receptor (TCR) engagement to provide free glutamine and fatty acids, including in people living with HIV-1 (PLWH). These nutrients fuel mitochondrial ATP generation through glutaminolysis and fatty acid oxidation (FAO) pathways, to fulfill the bioenergetic demands for optimal IL-21 and cytotoxic molecule production in CD4 and CD8 cells, respectively. Here, we expand our knowledge on how the metabolic events that occur in the mitochondria of virus-specific TM down-stream of the autophagy are regulated.
View Article and Find Full Text PDFGlucose-regulated protein 78 regulates the subunit-folding of the CCT complex by modulating gene expression and protein interaction in the microsporidian Nosema bombycis.
Int J Biol Macromol
December 2024
Jiangsu University of Science and Technology, Zhenjiang, People's Republic of China; Sericulture Research Institute, Chinese Academy of Agricultural Sciences, Zhenjiang, People's Republic of China. Electronic address:
Chaperonin containing tailless complex polypeptide 1 (CCT) functions as a molecular chaperone and is essential for ensuring proper protein folding. Glucose-regulated protein 78 (GRP78/Bip), also a type of chaperone, not only assists in folding of proteins, but also facilitates the transportation of proteins into the endoplasmic reticulum (ER) via the Sec protein complex. In this study, we identified the CCTη of N.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!