AURA: Accelerating drug discovery with accuracy, utility, and rank-order assessment for data-driven decision making.

Biopharmaceutical companies generate a wealth of data, ranging from in silico physicochemical properties and machine learning models to both low and high-throughput in vitro assays and in vivo studies. To effectively harnesses this extensive data, we introduce a statistical methodology facilitated by Accuracy, Utility, and Rank Order Assessment (AURA), which combines basic statistical analyses with dynamic data visualizations to evaluate endpoint effectiveness in predicting intestinal absorption. We demonstrated that various physicochemical properties uniquely influence intestinal absorption on a project-specific basis, considering factors like intestinal efflux, passive permeability, and clearance.

Discovery of Potent Azetidine-Benzoxazole MerTK Inhibitors with Target Engagement.

Inhibition of the receptor tyrosine kinase MerTK by small molecules has the potential to augment the immune response to tumors. Potent, selective inhibitors with high levels of target engagement are needed to fully evaluate the potential use of MerTK inhibitors as cancer therapeutics. We report the discovery and optimization of a series of pyrazinamide-based type 1.

Discovery of A-910, a Highly Potent and Orally Bioavailable Dual MerTK/Axl-Selective Tyrosine Kinase Inhibitor.

TAM receptor tyrosine kinases have emerged as promising therapeutic targets for cancer treatment due to their roles in both tumor intrinsic survival mechanisms and suppression of antitumor immunity within the tumor microenvironment. Inhibiting MerTK and Axl selectively is believed to hinder cancer cell survival, reverse the protumor myeloid phenotype, and suppress efferocytosis, thereby eliciting an antitumor immune response. In this study, we present the discovery of , a highly potent and selective dual MerTK/Axl inhibitor, achieved through a structure-based medicinal chemistry campaign.

High-Throughput SFC-MS/MS Method to Measure EPSA and Predict Human Permeability.

Permeability is a key factor driving the absorption of orally administered drugs. In early discovery, the efficient evaluation of permeability, particularly for compounds violating Lipinski's Rule of 5, remains challenging. Addressing this, we established a high-throughput method to measure the experimental polar surface area (HT-EPSA) as an in vitro surrogate to measure permeability.

Integrity and efficiency: AbbVie's journey of building an integrated nonregulated bioanalytical laboratory.

While bioanalytical outsourcing is widely adopted in the pharmaceutical industry, AbbVie is one of the few large biopharmaceutical companies having an internal bioanalytical unit to support nearly all its drug metabolism and pharmacokinetic studies. This article highlights our experience and perspective in building an integrated and centralized laboratory to provide early discovery and preclinical-stage bioanalytical support with high operational efficiency, cost-effectiveness and data integrity. The advantages of in-house nonregulated bioanalytical support include better control of data quality, faster turnaround times, real-time knowledge sharing and troubleshooting, and lower near- and long-term costs.

Global Analysis of Models for Predicting Human Absorption: QSAR, , and Preclinical Models.

Models intended to predict intestinal absorption are an essential part of the drug development process. Although many models exist for capturing intestinal absorption, many questions still exist around the applicability of these models to drug types like "beyond rule of 5" (bRo5) and low absorption compounds. This presents a challenge as current models have not been rigorously tested to understand intestinal absorption.

Determination of IL-23 Pharmacokinetics by Highly Sensitive Accelerator Mass Spectrometry and Subsequent Modeling to Project IL-23 Suppression in Psoriasis Patients Treated with Anti-IL-23 Antibodies.

The pro-inflammatory cytokine interleukin (IL)-23 is a key modulator of the immune response, making it an attractive target for the treatment of autoimmune disease. Correspondingly, several monoclonal antibodies against IL-23 are either in development or approved for autoimmune indications such as psoriasis. Despite being a clinical validated target, IL-23 pharmacokinetics (e.

AhR activation underlies the CYP1A autoinduction by A-998679 in rats.

Xenobiotic-mediated induction of cytochrome P450 (CYP) drug metabolizing enzymes (DMEs) is frequently encountered in drug discovery and can influence disposition, pharmacokinetic, and toxicity profiles. The CYP1A subfamily of DMEs plays a central role in the biotransformation of several drugs and environmental chemicals. Autoinduction of drugs through CYP3A enzymes is a common mechanism for their enhanced clearance.

Identification of aminopyrazolopyridine ureas as potent VEGFR/PDGFR multitargeted kinase inhibitors.

Tumor angiogenesis is mediated by KDR and other VEGFR and PDGFR kinases. Their inhibition presents an attractive approach for developing anticancer therapeutics. Here, we report a series of aminopyrazolopyridine ureas as potent VEGFR/PDGFR multitargeted kinase inhibitors.

Liver-specific knockdown of JNK1 up-regulates proliferator-activated receptor gamma coactivator 1 beta and increases plasma triglyceride despite reduced glucose and insulin levels in diet-induced obese mice.

The c-Jun N-terminal kinases (JNKs) have been implicated in the development of insulin resistance, diabetes, and obesity. Genetic disruption of JNK1, but not JNK2, improves insulin sensitivity in diet-induced obese (DIO) mice. We applied RNA interference to investigate the specific role of hepatic JNK1 in contributing to insulin resistance in DIO mice.

Differences in the DNA sequences in the upstream attenuator region of erm(A) in clinical isolates of Streptococcus pyogenes and their correlation with macrolide/lincosamide resistance.

The regulatory regions of 52 erm(A) [formerly erm(TR)] clinical Streptococcus pyogenes isolates were studied. Differences in the upstream regulatory region of erm(A) correlated with macrolide/lincosamide resistance patterns. Nine macrolide/lincosamide/streptogramin B-resistant isolates had changes in the leader sequence of erm(A) including base changes, insertions, or deletions.

Comparison of emm typing and ribotyping with three restriction enzymes to characterize clinical isolates of Streptococcus pyogenes.

A total of 336 Streptococcus pyogenes isolates recently recovered from patients with pharyngitis from 13 countries were characterized by emm typing and riboprinting using an automated Riboprinter (Dupont/Qualicon) based on the patterns produced by three restriction enzymes, EcoRI, PstI, and HindIII. Three enzymes were necessary to increase the discrimination of ribogroups formed by each enzyme. A total of 40 ribogroups and 38 emm sequences (not counting allelic variations) were identified.

Community-based surveillance in the united states of macrolide-resistant pediatric pharyngeal group A streptococci during 3 respiratory disease seasons.

Background: In 2001, a total of 48% of pharyngeal group A streptococci (GAS) from Pittsburgh children were macrolide resistant. We assessed macrolide resistance, resistance genes, and emm types among GAS in the United States.

Methods: In prospective, multicenter, community-based surveillance of pharyngeal GAS recovered from children 3-18 years old during 3 respiratory seasons (the 2000-2001 season, the 2001-2002 season, and the 2002-2003 season), GAS were tested for macrolide resistance and underwent emm gene sequencing.

Characterization and prevalence of MefA, MefE, and the associated msr(D) gene in Streptococcus pneumoniae clinical isolates.

Recent work has shown that the efflux genes in Streptococcus pneumoniae that are responsible for acquired macrolide resistance can be distinguished as either mef(E) or mef(A). The genetic elements on which mef(A) and mef(E) are found also carry an open reading frame (ORF) that is 56% homologous to msr(A) in Staphylococcus. The prevalence of mef(A/E) and of the msr-like ORF [msr(D)] was evaluated in 153 mef(+) S.

Epidemiology of macrolide and/or lincosamide resistant Streptococcus pneumoniae clinical isolates with ribosomal mutations.

Twenty macrolide and/or lincosamide resistant Streptococcus pneumoniae clinical isolates from various sources with 50S ribosomal mutations were identified. Mutations were identified in the 23S rDNA with substitutions at A2058, A2059, or C2611 and in L4 or L22 ribosomal protein genes. Fourteen were A2059G substitutions, one was A2058G, two were C2611T, two had an altered L4 and one isolate contained an altered L22 gene.

Molecular epidemiology of macrolide resistance in neonatal bloodstream isolates of group B streptococci.

Pulsed-field gel electrophoresis (PFGE) was performed on 122 neonatal bloodstream isolates of group B streptococci (GBS) to further examine the relationship between macrolide resistance and serotype V GBS (GBS-V). Over one-third (35%) of macrolide-resistant GBS belonged to a single PFGE subtype of GBS-V, which was also the most common GBS-V subtype noted in previous Centers for Disease Control and Prevention surveillance studies. Erm methylase (ermA and ermB) was the most common resistance mechanism detected, present in 12 of 20 macrolide-resistant GBS.

Comparison of in vitro activities of ABT-773 and telithromycin against macrolide-susceptible and -resistant streptococci and staphylococci.

The activity of a new ketolide, ABT-773, was compared to the activity of the ketolide telithromycin (HMR-3647) against over 600 gram-positive clinical isolates, including 356 Streptococcus pneumoniae, 167 Staphylococcus aureus, and 136 Streptococcus pyogenes isolates. Macrolide-susceptible isolates as well as macrolide-resistant isolates with ribosomal methylase (Erm), macrolide efflux (Mef), and ribosomal mutations were tested using the NCCLS reference broth microdilution method. Both compounds were extremely active against macrolide-susceptible isolates, with the minimum inhibitory concentrations at which 90% of the isolates tested were inhibited (MIC90s) for susceptible streptococci and staphylococci ranging from 0.