Reversible lysine-targeted probes reveal residence time-based kinase selectivity.

The expansion of the target landscape of covalent inhibitors requires the engagement of nucleophiles beyond cysteine. Although the conserved catalytic lysine in protein kinases is an attractive candidate for a covalent approach, selectivity remains an obvious challenge. Moreover, few covalent inhibitors have been shown to engage the kinase catalytic lysine in animals.

Phenotypic Characterization of Targeted Knockdown of Cyclin-Dependent Kinases in the Intestinal Epithelial Cells.

Cyclin-dependent kinases (CDKs) are serine/threonine kinases that regulate cell cycle and have been vigorously pursued as druggable targets for cancer. There are over 20 members of the CDK family. Given their structural similarity, selective inhibition by small molecules has been elusive.

Intestinal Toxicity in Rats Following Administration of CDK4/6 Inhibitors Is Independent of Primary Pharmacology.

Recently three different cyclin-dependent kinase 4 and 6 (CDK4/6) dual inhibitors were approved for the treatment of breast cancer (palbociclib, ribociclib, and abemaciclib), all of which offer comparable therapeutic benefits. Their safety profiles, however, are different. For example, neutropenia is observed at varying incidences in patients treated with these drugs; however, it is the most common adverse event for palbociclib and ribociclib, whereas diarrhea is the most common adverse event observed in patients treated with abemaciclib.

miR-208a as a biomarker of isoproterenol-induced cardiac injury in Sod2+/- and C57BL/6J wild-type mice.

This investigation examined microRNA-208a (miR-208a) as a potential biomarker of isoproterenol (ISO)-induced cardiac injury in superoxide dismutase-2 (Sod2(+/-) ) and the wild-type mice, and the potential sensitivity of Sod2(+/-) mice to ISO-induced toxicity. A single intraperitoneal injection of ISO was administered to age-matched wild-type and Sod2(+/-) mice at 0, 80, or 160 mg/kg. Plasma miR-208a, cardiac troponin I (cTnI), and ISO systemic exposure were measured at various time points postdose.

Responses of the steroidogenic pathway from exposure to methyl-tert-butyl ether and tert-butanol.

Methyl tertiary-butyl ether (MTBE) is a solvent and fuel additive included in reformulated gasoline to increase combustion efficiency. While widespread use in motor fuels in the U.S.

RTP801 gene expression is differentially upregulated in retinopathy and is silenced by PF-04523655, a 19-Mer siRNA directed against RTP801.

Purpose: The intraocular pharmacodynamics of PF-04523655, a small-interfering RNA (siRNA) directed against RTP801, was characterized using rat models of retinopathy.

Methods: Rat models of streptozotocin-induced diabetes and wet AMD were used to determine the onset, extent, and duration of siRNA inhibition of retinal RTP801 expression by PF-04523655, and this inhibition was characterized by pharmacokinetic/pharmacodynamic (PK/PD) modeling. A rat model of wet AMD was also used to examine PF-04523655 dose-dependent effects on the incidence of clinical grade 3 or 4 choroidal neovascularization lesions.

Pan-FGFR inhibition leads to blockade of FGF23 signaling, soft tissue mineralization, and cardiovascular dysfunction.

The fibroblast growth factor receptors (FGFR) play a major role in angiogenesis and are desirable targets for the development of therapeutics. Groups of Wistar Han rats were dosed orally once daily for 4 days with a small molecule pan-FGFR inhibitor (5mg/kg) or once daily for 6 days with a small molecule MEK inhibitor (3mg/kg). Serum phosphorous and FGF23 levels increased in all rats during the course of the study.

A tyrosine kinase inhibitor-induced myocardial degeneration in rats through off-target phosphodiesterase inhibition.

PF-04254644 is a selective kinase inhibitor of mesenchymal epithelial transition factor/hepatocyte growth factor receptor with known off-target inhibitory activity against the phosphodiesterase (PDE) family. Rats given repeated oral doses of PF-04254644 developed a mild to moderate myocardial degeneration accompanied by sustained increase in heart rate and contractility. Investigative studies were conducted to delineate the mechanisms of toxicity.

Digoxin is not a substrate for organic anion-transporting polypeptide transporters OATP1A2, OATP1B1, OATP1B3, and OATP2B1 but is a substrate for a sodium-dependent transporter expressed in HEK293 cells.

Digoxin, an orally administered cardiac glycoside cardiovascular drug, has a narrow therapeutic window. Circulating digoxin levels (maximal concentration of ∼1.5 ng/ml) require careful monitoring, and the potential for drug-drug interactions (DDI) is a concern.

Effect of the multitargeted tyrosine kinase inhibitors imatinib, dasatinib, sunitinib, and sorafenib on mitochondrial function in isolated rat heart mitochondria and H9c2 cells.

Cardiovascular disease has recently been suggested to be a significant complication of cancer treatment with several kinase inhibitors. In some cases, the mechanisms leading to cardiotoxicity are postulated to include mitochondrial dysfunction, either as a primary or secondary effect. Detecting direct effects on mitochondrial function, such as uncoupling of oxidative phosphorylation or inhibition of electron transport chain components, as well as identifying targets within the mitochondrial electron transport chain, can be accomplished in vitro.

First-in-class pan caspase inhibitor developed for the treatment of liver disease.

A series of oxamyl dipeptides were optimized for pan caspase inhibition, anti-apoptotic cellular activity and in vivo efficacy. This structure-activity relationship study focused on the P4 oxamides and warhead moieties. Primarily on the basis of in vitro data, inhibitors were selected for study in a murine model of alpha-Fas-induced liver injury.

Characterization of IDN-6556 (3-[2-(2-tert-butyl-phenylaminooxalyl)-amino]-propionylamino]-4-oxo-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid): a liver-targeted caspase inhibitor.

The potency, efficacy, and pharmacokinetic properties of IDN-6556 (3-[2-[(2-tert-butyl-phenylaminooxalyl)-amino]-propionylamino]-4-oxo-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid), a first-in-class caspase inhibitor in clinical trials for the treatment of liver diseases, were characterized in vivo in rodent models. In the mouse alpha-Fas model of liver injury, i.p.