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 >

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 >

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/

The 3C-like protease (3CLpro) is an essential enzyme for the replication of SARS-CoV-2 and thus is a target for drug discovery teams. Nearly all inhibitors of coronavirus 3CLpro reported so far are covalent inhibitors. Here, we report the development of specific, noncovalent inhibitors of 3CLpro with high in vivo efficacy in mice. One compound, WU-04, …Read More >

WuXi AppTec scientists recently contributed to a research study published in the journal Hepatology, characterizing the efficacy of prodrug DF-006 for treating chronic hepatitis B infection. DF-006 is an orally active agonist of alpha‐kinase 1, a pattern recognition receptor involved in the stimulation of innate immunity.  The authors show that DF‐006 is efficacious in hepatitis …Read More >

WuXi AppTec scientists recently contributed to a research article in the Journal of Medicinal Chemistry describing the optimization of a piperidine series of small molecules as novel allosteric activators of PKG1α (a compelling drug target for treatment of cardiovascular diseases).  This study reveals a mechanism of action for these compounds consistent with cGMP-induced activation, including …Read More >

WuXi AppTec scientists recently contributed to a research article in the Royal Society of Chemistry describing the large-scale synthesis of a potent and selective inhibitor of Notum carboxylesterase (an enzyme that suppresses Wnt signaling pathways).  By employing a modified Sakai reaction as the key step, a one-pot synthesis of this Notum inhibitor was developed, enabling …Read More >

Expansion of the E3 ligase toolbox has the potential to dramatically advance the field of targeted protein degradation.  WuXi AppTec scientists recently contributed to a research article in the Journal of Medicinal Chemistry describing the discovery of novel small molecule binders of GID4, a substrate receptor in the human CTLH E3 ligase complex.  Researchers used …Read More >

Delivery carriers are a critical component in the development of mRNA vaccines. Here, we describe the synthesis of a cationic polymer as a carrier for mRNA cancer vaccine delivery. In vivo results show that this polymer-based mRNA vaccine significantly delays tumor growth after vaccination of mice. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9743697/