Evaluation of Cereblon-Directing Warheads for the Development of Orally Bioavailable PROTACs.

PROTACs usually occupy physicochemical space outside the one defined by classical drug-like molecules, which often presents considerable challenges in their optimization and development for oral administration. We have previously reported phenyl glutarimide (PG)-based BET PROTAC SJ995973, with improved overall degradation and antiproliferative activities compared to its direct thalidomide-based analogue dBET1, but similarly poor pharmacokinetic profile. To further demonstrate the PG utility, we describe here optimization efforts that led to the discovery of an orally bioavailable BET-PROTAC SJ44236 (), and results of a comprehensive comparative study with analogues containing alternative CRBN-directing warheads.

Iron management and exercise training in individuals with chronic kidney disease: lived experiences.

Background: Non-anaemic iron deficiency is highly prevalent in people living with chronic kidney disease (CKD) but is underdiagnosed and undertreated, especially in earlier stages of CKD. A multicentre trial assessing the effect of intravenous iron supplementation in iron-deficiency but not anaemic people with CKD included a qualitative sub-study that aimed to explore the patient experience and psychosocial impact of living with CKD and iron deficiency, and the experience of the therapeutic intervention (intravenous iron and exercise).

Methods: Semi-structured interviews were conducted with 23 trial participants blinded to treatment.

International Nephrology Masterclass in Chronic Kidney Disease: Rationale, Summary, and Future Perspectives.

Chronic kidney disease (CKD) is a progressive condition that affects more than 10% of the population worldwide, accounting for more than 843 million (M) individuals. The prevalence of CKD (844 M patients) is higher than that of diabetes mellitus (422 M patients), cancer (42 M patients), and HIV (37 M patients), but people are often less aware of it. Global expert groups predict reductions in the nephrology workforce in the next decade, with a declining interest in nephrology careers.

PhpC transcription factor infiltrates heterochromatin to generate cryptic intron-containing transcripts crucial for small RNA production.

The assembly of repressive heterochromatin in eukaryotic genomes is crucial for silencing lineage-inappropriate genes and repetitive DNA elements. Paradoxically, transcription of repetitive elements within constitutive heterochromatin domains is required for RNA-based mechanisms, such as the RNAi pathway, to target heterochromatin assembly proteins. However, the mechanism by which heterochromatic repeats are transcribed has been unclear.

Medication review interventions for adults living with advanced chronic kidney disease: A scoping review.

Structured medication reviews (SMRs) were introduced into the National Health Service (NHS) Primary Care to support the delivery of the NHS Long-Term Plan for medicines optimization. SMRs improve the quality of care, reduce harm and offer value for money. However, evidence to support SMRs for patients with chronic kidney disease (CKD) stage G4-5D with elevated risk of cardiovascular disease and premature mortality is unknown.