Knowledge Library
Discovery of Novel GST Inhibitors Identified from a DNA-Encoded Library
WuXi AppTec scientists recently contributed to a study which led to the discovery and optimization of a novel series of GST inhibitors. The authors used affinity mediated DEL selection against a privileged scaffold to identify a compound with potent inhibition against SjGST and GSTM2. SAR studies, coupled with X-ray crystallography and structural analysis, revealed that …Read More >
Discovery and Characterization of Proteolysis Targeting Chimeras: Tissue Transglutaminase
Tissue transglutaminase (TG2) is a multifunctional enzyme activated in several pathological conditions, including cancer. WuXi AppTec recently contributed to a study which used a targeted protein degradation strategy to abolish TG2’s myriad of functions. The authors synthesized and characterized a series of VHL-based degraders that reduce TG2 in ovarian cancer cells in a proteasome-dependent manner.
Discovery and preclinical profile of LX-039, a novel indole-based oral selective estrogen receptor degrader (SERD)
WuXi AppTec scientists contributed to a study which identified a novel, indole-based, selective estrogen receptor degrader (SERD), designated LX-039. The authors show that LX-039 exhibits potent activity in ER degradation and proliferation assays. With favorable ADME/PK properties, LX-039 also exhibits higher efficacy in a tamoxifen-resistant MCF7 CDX model compared to fulvestrant, with up to 90% inhibition …Read More >
DELs enable the development of BRET probes for target engagement studies in cells
WuXi AppTec scientists recently contributed to a research article in Cell Chemical Biology demonstrating the successful conversion of ligands identified from DNA-encoded library (DEL) screening into highly functional, cell-active, bioluminescence resonance energy transfer (BRET) probes. The authors show that analyzing preliminary DEL hits based on target occupancy data generated in live, intact cells is an …Read More >
Inhibition of the hERG potassium ion channel by non-nucleoside CMV polymerase antiviral inhibitors
WuXi AppTec scientists collaborated on a study to characterize a series of pyrroloquinoline derivatives that were designed and synthesized to understand the effect of various substitutions on human cytomegalovirus (HCMV) polymerase activity, antiviral activity, and hERG inhibition. Results suggest that substitutions can be fine-tuned to reduce hERG inhibition while maintaining HCMV antiviral potency. The abstract …Read More >
TEAD Proteins Associate With DNA Repair Proteins to Facilitate Cellular Recovery
WuXi AppTec scientists recently contributed to a research study which utilized an affinity purification mass spectrometry approach to identify nuclear interacting partners of Transcriptional Enhanced Associate Domain (TEAD) proteins. The authors found a significant enrichment of interacting proteins linked to DNA damage, and they showed that depletion of TEAD transcription factors makes cells more susceptible …Read More >
DNA-Encoded Macrocyclic Peptide Libraries Enable the Discovery of a Neutral MDM2–p53 Inhibitor
Macrocyclic peptides are an emerging molecular class for targeting intracellular protein–protein interactions (PPIs) and for providing an oral modality for drug targets. Herein, we use DNA-encoded cyclic peptide libraries to discover a neutral nonapeptide, UNP-6457, that inhibits MDM2–p53 interaction with an IC50 of 8.9 nM. These studies showcase how tailored DEL libraries can directly yield …Read More >
Discovery of Potent and Selective Dual Leucine Zipper Kinase/Leucine Zipper-Bearing Kinase Inhibitors
Dual leucine zipper kinase (DLK) and leucine zipper-bearing kinase (LZK) have emerged as key regulators of neuronal degeneration and axon growth. WuXi AppTec scientists recently contributed to a research article in the Journal of Medicinal Chemistry demonstrating the use of ligand- and structure-based drug design approaches to discover an amino-pyrazine chemical series of DLK and …Read More >
Discovery and preclinical evaluations of GST-HG131, a novel HBV antigen inhibitor for the treatment of chronic hepatitis B infection
Chronic HBV infection (CHB) is a major contributor to liver-related deaths worldwide. The ultimate endpoint of CHB treatment is sustained HBV surface antigen (HBsAg) loss. Here, we report the design of a series of HBV surface antigen inhibitors which promotes reduction of HBV antigens in vitro and in vivo. https://pubmed.ncbi.nlm.nih.gov/36089112/