The VEGFR/PDGFR tyrosine kinase inhibitor, ABT-869, blocks necroptosis by targeting RIPK1 kinase.

Necroptosis is a mode of programmed, lytic cell death that is executed by the mixed lineage kinase domain-like (MLKL) pseudokinase following activation by the upstream kinases, receptor-interacting serine/threonine protein kinase (RIPK)-1 and RIPK3. Dysregulated necroptosis has been implicated in the pathophysiology of many human diseases, including inflammatory and degenerative conditions, infectious diseases and cancers, provoking interest in pharmacological targeting of the pathway. To identify small molecules impacting on the necroptotic machinery, we performed a phenotypic screen using a mouse cell line expressing an MLKL mutant that kills cells in the absence of upstream death or pathogen detector receptor activation. This screen identified the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) tyrosine kinase inhibitor, ABT-869 (Linifanib), as a small molecule inhibitor of necroptosis. We applied a suite of cellular, biochemical and biophysical analyses to pinpoint the apical necroptotic kinase, RIPK1, as the target of ABT-869 inhibition. Our study adds to the repertoire of established protein kinase inhibitors that additionally target RIPK1 and raises the prospect that serendipitous targeting of necroptosis signalling may contribute to their clinical efficacy in some settings.

Contemporary national and international guidelines on physical activity and sedentary behaviour for people living with chronic conditions, disability and advanced age: a scoping review.

OBJECTIVES: Physical activity guidelines inform policy and practice in promoting healthier lifestyles. The WHO advocates for distinct recommendations for each country to address variation in needs, resources and context. Specific regional recommendations for three underactive populations facing unique barriers to movement are lacking-people with chronic conditions, disability and advanced age. We review which countries/regions provide specific physical activity guidelines for these populations to identify deficiencies in meeting WHO recommendations and inform future directions for guideline development. DESIGN: Scoping review. DATA SOURCES: OVID Medline, PubMed, Scopus, Embase, Web of Science, Google Scholar, ProQuest, CINAHL, Google searches, targeted websites. ELIGIBILITY CRITERIA: Data sources were searched from database inception to September 2023 to identify community-facing physical activity guidelines at the national/international level for these populations. We recorded, summarised and analysed physical activity guideline recommendations extracted from published guideline documents, organised by population and country/region. RESULTS: 66 articles were identified, addressing 28 distinct countries/regions, including four international guidelines, published from 2009 to 2023. The WHO guidelines were adopted by 19 countries and the European Union. Across all regions, a lack of specific advice was identified for individuals with chronic conditions (46%), disability (46%) and advanced age (11%). Advice for chronic conditions and disability commonly replicated general adult population advice. CONCLUSION: Many countries/regions do not produce physical activity guidelines specific to populations with chronic conditions and disability. As such, a large proportion of countries/regions failed to meet WHO recommendations, highlighting a lack of customised advice to address unique barriers faced by vulnerable populations.