Small molecule APOL1 inhibitors as a precision medicine approach for APOL1-mediated kidney disease.

Chronic kidney disease affects ~10% of people worldwide and there are no disease modifying therapeutics that address the underlying cause of any form of kidney disease. Genome wide association studies have identified the G1 and G2 variants in the apolipoprotein L1 (APOL1) gene as major contributors to a subtype of proteinuric kidney disease now referred to as APOL1-mediated kidney disease (AMKD). We hypothesized that inhibition of APOL1 could have therapeutic potential for this genetically-defined form of kidney disease.

[Motivational factors for early option choice by laboratory medicine residents in France].

In France, both students from medicine and pharmacy background can have access to the residency in laboratory medicine (LM). The current curriculum of LM residency includes an early choice of option after the first two years of residency, which subsequently guides the rest of the training. This study aimed to analyze these choice and motivational factors, since its implementation in 2017.

Absorption, Metabolism, and Excretion of [C]-Tolebrutinib After Oral Administration in Humans, Contribution of the Metabolites to Pharmacological Activity.

Background And Objective: Tolebrutinib is a covalent inhibitor of Bruton's tyrosine kinase, an enzyme expressed in B lymphocytes and myeloid cells including microglia, which are thought to be major drivers of inflammation in multiple sclerosis. This excretion balance and metabolism study evaluated the metabolite profile of tolebrutinib in healthy male volunteers.

Methods: Six healthy volunteers received a 60-mg oral dose of [C]-tolebrutinib, and metabolite profiling of C-labeled metabolites was performed using a combination of liquid chromatography, mass spectrometry, and radioactivity assay methods.

Identification of , an Orally Bioavailable Compound that Inhibits the DNA Polymerase Activity of Polθ.

DNA polymerase theta (Polθ) is an attractive synthetic lethal target for drug discovery, predicted to be efficacious against breast and ovarian cancers harboring BRCA-mutant alleles. Here, we describe our hit-to-lead efforts in search of a selective inhibitor of human Polθ (encoded by POLQ). A high-throughput screening campaign of 350,000 compounds identified an 11 micromolar hit, giving rise to the N2-substituted fused pyrazolo series, which was validated by biophysical methods.

CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition.

Amplification of the CCNE1 locus on chromosome 19q12 is prevalent in multiple tumour types, particularly in high-grade serous ovarian cancer, uterine tumours and gastro-oesophageal cancers, where high cyclin E levels are associated with genome instability, whole-genome doubling and resistance to cytotoxic and targeted therapies. To uncover therapeutic targets for tumours with CCNE1 amplification, we undertook genome-scale CRISPR-Cas9-based synthetic lethality screens in cellular models of CCNE1 amplification. Here we report that increasing CCNE1 dosage engenders a vulnerability to the inhibition of the PKMYT1 kinase, a negative regulator of CDK1.