Discovery of 6-Fluoro-5-{4-[(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl]piperazin-1-yl}--methylpyridine-2-carboxamide (AZD9574): A CNS-Penetrant, PARP1-Selective Inhibitor.

PARP inhibitors have attracted considerable interest in drug discovery due to the clinical success of first-generation agents such as olaparib, niraparib, rucaparib, and talazoparib. Their success lies in their ability to trap PARP to DNA; however, first-generation PARP inhibitors were not strictly optimized for trapping nor for selectivity among the PARP enzyme family. Previously we described the discovery of the second-generation PARP inhibitor AZD5305, a selective PARP1-DNA trapper.

Prosthetic Condyle with Concurrent Microvascular Reconstruction for Mandibular Disarticulation Defects: A Retrospective Series.

Introduction: Reconstruction of mandibular disarticulation defects is a challenging area of head and neck surgery, with a variety of options available for replacement of the condylar head. The gold standard is autogenous reconstruction of the condyle-ramus unit. The use of a prosthetic condylar head is controversial, but in challenging cases, and those with a likely poor prognosis it may be considered and can achieve a good functional result.

Discovery of the First Clinical Protein Degrader for the Treatment of Autoimmune Indications: Orally Bioavailable and Selective IRAK4 Degrader KT-474.

IRAK4 inhibitors have been sought for the treatment of a host of diseases, however, recent evidence suggests a protein degradation approach might have advantages over an inhibitor. This viewpoint summarizes the discovery of KT-474─a selective and orally bioavailable interleuken receptor-associated kinase 4 proteolysis-targeting chimera in Phase 2 clinical trials for autoimmune indications.

Barriers and Facilitators to Implementing Health Literacy Practices in a Pediatric ENT Clinic: A Mixed-Methods Study.

Background: Despite strong evidence of improved patient outcomes, clinicians have been slow to adopt health literacy practices.

Purpose: To identify facilitators and barriers to implementing health literacy practices into clinical care.

Methods: Stakeholders (N = 40) completed surveys of acceptability, appropriateness, feasibility, conviction, and confidence with teach-back practices.

Discovery of a Potent and Selective Tyrosine Kinase 2 Inhibitor: TAK-279.

TYK2 is a key mediator of IL12, IL23, and type I interferon signaling, and these cytokines have been implicated in the pathogenesis of multiple inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, lupus, and inflammatory bowel diseases. Supported by compelling data from human genome-wide association studies and clinical results, TYK2 inhibition through small molecules is an attractive therapeutic strategy to treat these diseases. Herein, we report the discovery of a series of highly selective pseudokinase (Janus homology 2, JH2) domain inhibitors of TYK2 enzymatic activity.