R256 / Rigel, AstraZeneca - LARVOL DELTA

AZD0449, an inhaled JAK1 inhibitor, in healthy participants and patients with mild asthma. (PubMed, Br J Clin Pharmacol) - P1 | "AZD0449 was safely administered via inhalation, with low systemic exposure and lung retention. This study provides a greater understanding of inhaled dosing of small molecule JAK1 inhibitors for the treatment of asthma. No effect on PD biomarkers (FeNO and STAT6) was observed."

Journal • Asthma • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • STAT6

How should we prioritise genetic testing for kidney stone disease? (ERA 2025) - "Although based on a small and highly selected sample of patients, this study highlights that genetic testing is more likely to yield a positive outcome in patients who form stones at young age and/or have nephrocalcinosis. A composite score, which combines and weights multiple parameters, may also be a clinically useful method of prioritising those patients who should receive the R256 genomic medicine test. This is important because determining the sensitivity of genetic screening in all stone formers would require the entire cohort to be tested, which is neither practical nor cost effective."

Genetic Disorders • Metabolic Disorders • Nephrology • Renal Calculi

CARM1 methylates glioblastoma tumor suppressor Quaking to regulate its transcriptional coactivator function (SNO 2024) - "Through mutagenesis studies, we identified arginine 242 (R242) and arginine 256 (R256) as specific CARM1-mediated methylation sites on Qki...Moreover, brain-specific deletion of CARM1 in vivo results in neurological phenotypes reminiscent of Qki deletion. Altogether, we provide evidence that CARM1 represents a novel tumor suppressor in GBM that functions through the arginine methylation of Qki."

Brain Cancer • CNS Tumor • Glioblastoma • Metabolic Disorders • Oncology • Solid Tumor

CARM1 is a novel tumor suppressor in glioblastoma that regulates Qki through arginine methylation (SNO 2023) - "Within the QRD, we identified arginine 242 (R242) and arginine 256 (R256) as specific CARM1-mediated methylation sites on Qki. Mutations to these sites compromise Qki transcriptional activity, as Qki methylation mutant-expressing GSCs exhibited downregulation of Qki target genes compared to those expressing wildtype Qki. Taken together, we provide evidence that CARM1 functions as a tumor suppressor in GBM through a novel mechanism of Qki dysregulation."

Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Metabolic Disorders • Oncology • Solid Tumor • PTEN • QKI • TP53

Characterization of Selective and Potent JAK1 Inhibitors Intended for the Inhaled Treatment of Asthma. (PubMed, Drug Des Devel Ther) - "AZD0449 and AZD4604 show potential as inhibitors of signaling pathways involved in asthmatic immune responses, with target engagement demonstrated locally in the lung. These findings support the clinical development of AZD0449 and AZD4604 for the treatment of patients with asthma."

Journal • Asthma • Eosinophilia • Immunology • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases • IL13 • IL5 • STAT3 • STAT5 • TSLP

Experimental and in silico studies of competitive inhibition of family GH10 Aspergillus fumigatus xylanase A by Oryza sativa xylanase inhibitor protein. (PubMed, Int J Biol Macromol) - "Intermolecular hydrogen bonds T104/V99-Q5, R256-E235, D155-Y243 and D145-R194 on the upper of the TIM barrel were essential for strengthening the stability of complex. Therefore, these non-covalent interactions (NCI) played key role in the interaction between AfXylA10 and OsXIP."

Journal

A Study in Healthy Volunteers and Patients With Mild Asthma to Investigate the Safety, Anti-inflammatory Effect of Inhaled AZD0449 (clinicaltrials.gov) - P1; N=131; Completed; Sponsor: AstraZeneca; Recruiting ➔ Completed

Clinical • Trial completion • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

Methylated HNRNPK acts on RPS19 to regulate ALOX15 synthesis in erythropoiesis. (PubMed, Nucleic Acids Res) - "Dimethylation of residues R256, R258 and R268 in HNRNPK affects its interaction with RPS19. In noninduced K562 cells, RPS19 depletion results in the induction of ALOX15 synthesis and mitochondria degradation. Interestingly, residue W52 in RPS19, which is frequently mutated in Diamond-Blackfan Anemia (DBA), participates in specific HNRNPK binding and is an integral part of a putative aromatic cage."

Journal • Hematological Disorders • HNRNPK

An intra-bacterial activity for a T3SS effector. (PubMed, Sci Rep) - "While performing mass spectrometry experiments to identify glycosylation substrates of NleB orthologs, we unexpectedly observed that the bacterial glutathione synthetase (GshB) is glycosylated by NleB on arginine residue R256. NleB-mediated glycosylation of GshB resulted in enhanced GshB activity, leading to an increase in glutathione production, and promoted C. rodentium survival in oxidative stress conditions. These data represent, to our knowledge, the first intra-bacterial activity for a T3SS effector and show that arginine-GlcNAcylation, once thought to be restricted to host cell compartments, also plays an important role in regulating bacterial physiology."

Journal

A Study in Healthy Volunteers and Patients With Mild Asthma to Investigate the Safety, Anti-inflammatory Effect of Inhaled AZD0449 (clinicaltrials.gov) - P1; N=126; Recruiting; Sponsor: AstraZeneca; Trial completion date: Jan 2021 ➔ Apr 2021; Trial primary completion date: Jan 2021 ➔ Apr 2021

Clinical • Trial completion date • Trial primary completion date • Asthma • Respiratory Diseases

Actin R256 Mono-methylation Is a Conserved Post-translational Modification Involved in Transcription. (PubMed, Cell Rep) - "Further, gene expression and protein interaction studies uncover extensive correlations between actin R256me1 and active transcription. The discovery of actin R256me1 mark suggests a fundamental mechanism to distinguish nuclear actin from cytoplasmic actin through post-translational modification (PTM) and potentially implicates an actin PTM mark in transcription and human diseases."

Journal • PRMT5

[VIRTUAL] Profiling the impact of two JAK inhibitors in a pre-clinical model of allergic asthma (ERS 2020) - "These data indicate that JAK inhibition may be of benefit to patients suffering from allergic asthma."

Asthma • Immunology • Pneumonia • Respiratory Diseases • IL13 • IL4 • IL5 • IL9

A Study in Healthy Volunteers and Patients With Mild Asthma to Investigate the Safety, Anti-inflammatory Effect of Inhaled AZD0449 (clinicaltrials.gov) - P1; N=126; Recruiting; Sponsor: AstraZeneca; Active, not recruiting ➔ Recruiting; Trial completion date: Jul 2020 ➔ Jan 2021; Trial primary completion date: Jul 2020 ➔ Jan 2021

Clinical • Enrollment open • Trial completion date • Trial primary completion date • Asthma • Respiratory Diseases

Rigel announces fourth quarter and year end 2011 financial results (Rigel) - R256, inhaled IL-13 inhibitor is in preclinical studies aimed at evaluating its ability to reduce airway inflammation generally associated with chronic asthma & potentially improve the health of the lungs

New drug candidate • Immunology

A Study in Healthy Volunteers and Patients With Mild Asthma to Investigate the Safety, Anti-inflammatory Effect of Inhaled AZD0449. (clinicaltrials.gov) - P1; N=120; Active, not recruiting; Sponsor: AstraZeneca; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Asthma • Immunology • Respiratory Diseases • CRP

A Study in Healthy Volunteers and Patients With Mild Asthma to Investigate the Safety, Anti-inflammatory Effect of Inhaled AZD0449. (clinicaltrials.gov) - P1; N=120; Recruiting; Sponsor: AstraZeneca; N=174 ➔ 120

Clinical • Enrollment change • CRP

"And does $AZN have (an)other(s)? R256 & LAS194046" (@JacobPlieth)