Use of the dTAG system in vivo to degrade CDK2 and CDK5 in adult mice and explore potential safety liabilities.

The degradation tag (dTAG) system for target protein degradation can remove proteins from biological systems without the drawbacks of some genetic methods, such as slow kinetics, lack of reversibility, low specificity, and the inability to titrate dosage. These drawbacks can make it difficult to compare toxicity resulting from genetic and pharmacological interventions, especially in vivo. Because the dTAG system has not been studied extensively in vivo, we explored the use of this system to study the physiological sequalae resulting from CDK2 or CDK5 degradation in adult mice.

Editor's Highlight: Plasma miR-183/96/182 Cluster and miR-124 are Promising Biomarkers of Rat Retinal Toxicity.

Retinal toxicity is one of the leading causes of attrition in drug development, and drug-induced retinal toxicity remains an issue in both drug discovery and postmarketed drugs. Derisking strategies to help with early identification of retinal injury utilizing a predictive retinal miRNA biomarker would greatly benefit decision-making in drug discovery programs, ultimately reducing attrition due to retinal toxicity. Our previous work demonstrated elevation of circulating retina-enriched miRNAs in a retinal toxicity model.

Application of electroretinography (ERG) in early drug development for assessing retinal toxicity in rats.

Retinal ocular toxicity is among the leading causes of drug development attrition in the pharmaceutical industry. Electroretinography (ERG) is a non-invasive functional assay used to assess neuro-retinal physiological integrity by measuring the electrical responses. To directly assess the utility of ERG, a series of studies was conducted following intravitreal and/or iv administration of pan-cyclin-dependent kinase inhibitors: AG-012,986 and AG-024,322 in rats.

An assessment of the ocular safety of excipient maleic acid following intravitreal injection in rabbits.

Maleic acid was formulated in 0.7% saline and injected intravitreally in rabbits in order to evaluate ocular safety and tolerability. Maleic acid was formulated within a narrow pH range (2-3), administered in a fixed volume (100 µl), and concentrations ranged from 0.

Cardiovascular effects in rats following exposure to a receptor tyrosine kinase inhibitor.

The receptor tyrosine kinase receptor (RTK) signaling pathway, mesenchymal-epithelial transition factor (c-Met)/hepatocyte growth factor receptor (HGFR), has been implicated in oncogenesis and is a target of interest in cancer therapy. PF-04254644 is a potent and selective inhibitor of c-Met/HGFR. Wide ligand binding profiling of PF-04254644 revealed a potentially significant interaction with phosphodiesterase (PDE) 3, and follow-up PDE enzyme activity assays confirmed PF-04254644 as a potent inhibitor of PDE3 as well as other PDEs (1, 2, 5, 10, and 11).

PD0325901, a mitogen-activated protein kinase kinase inhibitor, produces ocular toxicity in a rabbit animal model of retinal vein occlusion.

Objective: PD0325901, a selective inhibitor of mitogen-activated protein kinase kinase (MEK), was associated with the occurrence of ocular retinal vein occlusion (RVO) during clinical trials in patients with solid tumors. As previous animal safety studies in rats and dogs did not identify the eye as a target organ of toxicity, this work was conducted to develop a rabbit model of ocular toxicity with PD0325901.

Methods: Dutch-Belted rabbits were administered a single intravitreal injection of PD0325901 (0.