Using PD325901 as a starting point for identifying novel allosteric MEK inhibitors with high cell potency and long-lasting target inhibition in vivo, truncation of its hydroxamic ester headgroup was combined with incorporation of alkyl and aryl ethers at the neighboring ring position. Whereas alkoxy side chains did not yield sufficient levels of cell potency, specifically substituted aryloxy groups allowed for high enzymatic and cellular potencies. Sulfamide 28 was identified as a highly potent MEK inhibitor with nanomolar cell potency against B-RAF (V600E) as well as Ras-mutated cell lines, high metabolic stability and resulting long half-lives. It was efficacious against B-RAF as well as K-Ras driven xenograft models and showed-despite being orally bioavailable and not a P-glycoprotein substrate-much lower brain/plasma exposure ratios than PD325901.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bmcl.2013.02.028 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
The independent predictive value of admission serum ferritin concentration for prognosis in elderly patients with community-acquired pneumonia in the emergency department.
Front Cell Infect Microbiol
January 2025
Emergency Medicine Clinical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
Background: Community-acquired pneumonia (CAP) poses a significant health threat to the elderly population, leading to high morbidity and mortality rates. Serum ferritin, a critical indicator of iron metabolism, plays a pivotal role in inflammation and immune regulation. Nevertheless, its specific prognostic relevance in elderly patients with CAP remains unclear.
View Article and Find Full Text PDFSynthesis, Characterization, and Antimicrobial Activity of Urea-Containing α/β Hybrid Peptides against and Methicillin-Resistant .
ACS Omega
January 2025
Infectious Diseases Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, Jammu and Kashmir 180001, India.
The insertion of β-amino acids and replacement of the amide bond with a urea bond in antimicrobial peptide sequences are promising approaches to enhance the antibacterial activity and improve proteolytic stability. Herein, we describe the synthesis, characterization, and antibacterial activity of short αβ cationic hybrid peptides LA-Orn-βAcc-PEA, ; LA-Lys-βAcc-PEA, ; and LA-Arg-βAcc-PEA, in which a C12 lipid chain is conjugated at the N terminus of peptide through urea bonds. Further, we evaluated all the peptides against both and methicillin-resistant (MRSA) and their multidrug resistant (MDR) clinical isolates.
View Article and Find Full Text PDFLatrunculin U: a potent actin-disrupter from the Red Sea marine sponge .
Nat Prod Res
January 2025
Department of Pharmacology and Mays Cancer Center, University of Texas Health Science Center, San Antonio, Texas, USA.
During our efforts to identify biologically active compounds from Red Sea marine invertebrates, a new compound, latrunculin U (), was identified from the Red Sea sponge along with latrunculins A (), B (), and 16--latrunculin B (). The structures of the latrunculins were elucidated based on a combination of comprehensive 1D and 2D NMR analyses and high-resolution mass spectral determinations. The antiproliferative potency of each compound in HeLa cells was evaluated, and they had IC values ranging from 0.
View Article and Find Full Text PDFAntiviral effects and mechanism of Qi pi pill against influenza viruses.
Animal Model Exp Med
January 2025
Qingdao Academy of Chinese Medicinal Sciences, Shandong University of Traditional Chinese Medicine, Qingdao, Shandong, China.
Background: Qi pi pill (QPP), which contains Renshen, Baizhu, Fuling, Gancao, Chenpi, Shanyao, Lianzi, Shanzha, Liushenqu, Maiya, and Zexie, was recommended for preventing and treating COVID-19 in Shandong Province (China). However, the mechanism by which QPP treats infectious diseases remains unclear. This study aims to investigate the therapeutic effect of QPP in vitro and on acute influenza infection in mice, exploring its mechanism of action against influenza A virus (IAV).
View Article and Find Full Text PDFA quantitative intracellular peptide binding assay reveals recognition determinants and context dependence of short linear motifs.
J Biol Chem
January 2025
Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA. Electronic address:
Transient protein-protein interactions play key roles in controlling dynamic cellular responses. Many examples involve globular protein domains that bind to peptide sequences known as Short Linear Motifs (SLiMs), which are enriched in intrinsically disordered regions of proteins. Here we describe a novel functional assay for measuring SLiM binding, called Systematic Intracellular Motif Binding Analysis (SIMBA).
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!