Mechanism of allosteric inhibition of human p97/VCP ATPase and its disease mutant by triazole inhibitors.

Human p97 ATPase is crucial in various cellular processes, making it a target for inhibitors to treat cancers, neurological, and infectious diseases. Triazole allosteric p97 inhibitors have been demonstrated to match the efficacy of CB-5083, an ATP-competitive inhibitor, in cellular models. However, the mechanism is not well understood.

Replacement of the hydroxamic acid group in the selective HDAC8 inhibitor PCI-34051.

PCI-34051 is a valuable tool to interrogate the therapeutic effects of selective inhibition of HDAC8. However, it has not advanced to clinical trials, perhaps due to poor PK or off-target effects. We hypothesized that the presence of a hydroxamic acid (HA) group in PCI-34051 contributed to its lack of advancement.

Optimization of 1,2,4-Triazole-Based p97 Inhibitors for the Treatment of Cancer.

The AAA+ ATPase p97 (valosin-containing protein, VCP) is a master regulator of protein homeostasis and therefore represents a novel target for cancer therapy. Starting from a known allosteric inhibitor, NMS-873, we systematically optimized this scaffold, in particular, by applying a benzene-to-acetylene isosteric replacement strategy, specific incorporation of F, and eutomer/distomer identification, which led to compounds that exhibited nanomolar biochemical and cell-based potency. In cellular pharmacodynamic assays, robust effects on biomarkers of p97 inhibition and apoptosis, including increased levels of ubiquitinated proteins, CHOP and cleaved caspase 3, were observed.

Structure-property relationships of fluorinated carboxylic acid bioisosteres.

Fluorinated alcohols and phenols are potentially useful as bioisosteres of the carboxylic acid functional group. To enable a direct comparison of the properties of fluorinated carboxylic acid surrogates with those of other commonly used, non-fluorinated bioisosteres, we conducted a structure-property relationship (SPR) study based on matched molecular pair (MMP) analyses. A series of representative examples have been characterized by experimentally determining physicochemical properties, such as acidity (pK), lipophilicity (logD), and permeability (PAMPA).

Validation of HDAC8 Inhibitors as Drug Discovery Starting Points to Treat Acute Kidney Injury.

Acute kidney injury (AKI), a sudden loss of kidney function, is a common and serious condition for which there are no approved specific therapies. While there are multiple approaches to treat the underlying causes of AKI, no targets have been clinically validated. Here, we assessed a series of potent, selective competitive inhibitors of histone deacetylase 8 (HDAC8), a promising therapeutic target in an AKI setting.

Affinity Capture of p97 with Small-Molecule Ligand Bait Reveals a 3.6 Å Double-Hexamer Cryoelectron Microscopy Structure.

Recent progress in the development of affinity grids for cryoelectron microscopy (cryo-EM) typically employs genetic engineering of the protein sample such as histidine or Spy tagging, immobilized antibody capture, or nonselective immobilization via electrostatic interactions or Schiff base formation. We report a powerful and flexible method for the affinity capture of target proteins for cryo-EM analysis that utilizes small-molecule ligands as bait for concentrating human target proteins directly onto the grid surface for single-particle reconstruction. This approach is demonstrated for human p97, captured using two different small-molecule high-affinity ligands of this AAA+ ATPase.

Identification of a Novel Oleic Acid Analog with Protective Effects in Multiple Cellular Models of Friedreich Ataxia.

Friedreich ataxia (FRDA) is an inherited neurodegenerative disorder for which there is no cure or approved treatment. It is characterized by the loss or impaired activity of frataxin protein, which is involved in the biogenesis of iron-sulfur clusters. Our previous studies suggested that cell death in FRDA may involve ferroptosis, an iron-dependent form of cell death requiring lipid peroxidation.

A Different Kind of Medicinal Chemistry Toolbox.

To attract and retain women in medicinal chemistry, a toolbox of resources and opportunities is suggested. Scientific meetings, books, affinity groups, training courses, and networks all can provide support and strategies to help increase the percentage of women in the field.

Author Correction: High-throughput identification of post-transcriptional utrophin up-regulators for Duchenne muscle dystrophy (DMD) therapy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

High-throughput identification of post-transcriptional utrophin up-regulators for Duchenne muscle dystrophy (DMD) therapy.

Upregulation of endogenous utrophin offers great promise for treating DMD, as it can functionally compensate for the lack of dystrophin caused by DMD gene mutations, without the immunogenic concerns associated with delivering dystrophin. However, post-transcriptional repression mechanisms targeting the 5' and 3' untranslated regions (UTRs) of utrophin mRNA significantly limit the magnitude of utrophin upregulation achievable by promoter activation. Using a utrophin 5'3'UTR reporter assay, we performed a high-throughput screen (HTS) for small molecules capable of relieving utrophin post-transcriptional repression.