Track topics on Twitter Track topics that are important to you
Cdc37 is known to work as a kinase-specific cochaperone, which selectively regulates the maturation of kinases through protein-protein interaction (PPI) with Hsp90. Directly disrupting the Hsp90-Cdc37 PPI is emerging as an alternative strategy to develop anticancer agents through a specific inhibition manner of kinase clients of Hsp90. Based on a first specific small molecule inhibitor targeting Hsp90-Cdc37 PPI (DDO-5936), which was previously reported by our group, we conducted a preliminary investigation of the structure-activity relationships and pharmacodynamic evaluations to improve the potency and drug-like properties. Here, our efforts resulted in a currently best inhibitor 18h with improved binding affinity (Kd = 0.5 μM) and cellular inhibitory activity (IC50 = 1.73 μM). Both in vitro and in vivo assays revealed 18h could efficiently block the Hsp90-Cdc37 interaction to specifically inhibit kinase clients of Hsp90. Furthermore, 18h showed ideal physiochemical properties with favorable stability, leading to an oral efficacy in vivo.
This article was published in the following journal.
Name: Journal of medicinal chemistry
Protein-RNA interactions mediate various cellular processes, whose dysregulation has been associated with a list of diseases. Thus, novel experimental tools for monitoring protein-RNA interactions are...
Monoclonal antibodies targeting the PD-1/PD-L1 immune checkpoint have emerged as efficient cancer biotherapeutics. In parallel, small molecules targeting PD-L1 are actively searched to offer novel the...
Modulating disease-relevant protein-protein interactions (PPIs) using small-molecule inhibitors is a quite indispensable diagnostic and therapeutic strategy in averting pathophysiological cues and dis...
Targeted protein degradation using chimeric small molecules such as proteolysis-targeting chimeras (PROTACs) and specific and nongenetic inhibitors of apoptosis protein [IAP]-dependent protein erasers...
Targeting the γ-aminobutyric acid type B (GABAB) receptor complex: Development of inhibitors targeting the K+ channel tetramerization domain (KCTD) containing proteins/GABAB receptor protein-protein interaction.
Targeting multi-protein receptor complexes, rather than receptors directly, is a promising concept in drug discovery. This is particularly relevant to the GABAB receptor complex, which plays a promine...
The purpose of the study is to better understand the function of asthma and COPD, and response to therapy. There are two Phases to this study broken into two arms. In Phase I, our propose ...
This study was designed to obtain information about the effect of new combinations of dairy proteins, in small servings with high protein concentrations, on postprandial amino acid kinetic...
The investigators examined the effects of dietary protein intake in a mixed meal at two levels of protein amount on whole body protein metabolisms in older adults.
In this study, we will explore the feasibility of doing a randomized controlled trial in our Intensive care department, King Abdulaziz Medical City, Riyadh which will test a two-step appro...
To establish therapeutic dendritic cell (DC) vaccines targeting HPV 16/18 E6/E7 protein to block the progression of CIN1/CIN2 to cervical cancer and evaluate the safety and efficacy of the...
Ligand-binding assays that measure protein-protein, protein-small molecule, or protein-nucleic acid interactions using a very large set of capturing molecules, i.e., those attached separately on a solid support, to measure the presence or interaction of target molecules in the sample.
Large collections of small molecules (molecular weight about 600 or less), of similar or diverse nature which are used for high-throughput screening analysis of the gene function, protein interaction, cellular processing, biochemical pathways, or other chemical interactions.
Protein interaction domains of about 70-90 amino acid residues, named after a common structure found in PSD-95, Discs Large, and Zona Occludens 1 proteins. PDZ domains are involved in the recruitment and interaction of proteins, and aid the formation of protein scaffolds and signaling networks. This is achieved by sequence-specific binding between a PDZ domain in one protein and a PDZ motif in another protein.
Protein modules with conserved ligand-binding surfaces which mediate specific interaction functions in SIGNAL TRANSDUCTION PATHWAYS and the specific BINDING SITES of their cognate protein LIGANDS.
Screening techniques first developed in yeast to identify genes encoding interacting proteins. Variations are used to evaluate interplay between proteins and other molecules. Two-hybrid techniques refer to analysis for protein-protein interactions, one-hybrid for DNA-protein interactions, three-hybrid interactions for RNA-protein interactions or ligand-based interactions. Reverse n-hybrid techniques refer to analysis for mutations or other small molecules that dissociate known interactions.
Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...