Receptor-interacting protein kinase 1 (RIPK1) is a serine/threonine kinase involved in the TNF signaling pathway and is a key regulator of cell death and inflammation. Aberrant RIPK1 activation has been implicated in microglial dysfunction and the pathogenesis of Alzheimer's disease. Inhibition of RIPK1 kinase activity enables selective modulation of the TNFR1 pathway and has been shown to protect against neuronal cell death in multiple animal models of human disease. Thus, inhibition of RIPK1 kinase activity appears to be an appealing therapeutic strategy for a range of neurodegenerative and autoimmune diseases. We report the discovery of a novel class of allosteric RIPK1 inhibitors developed using a knowledge-based approach. Optimization of the core structure of the hit compound, followed by lead optimization utilizing structure-based design led to the discovery of IACS-052584, a potent, orally bioavailable, and brain-penetrating RIPK1 inhibitor with excellent pharmacokinetics. IACS-052584 also displayed exquisite kinase selectivity and robust target engagement, which was characterized using markers of RIPK1 activity. In vivo studies using IACS-052584 demonstrated excellent activity in blocking TNF-dependent cellular responses as well as multiple peripheral and neuronal proinflammatory transcripts. In addition, It also significantly suppressed the disease-associated microglia (DAM) phenotype in mouse models of Alzheimer's disease, highlighting its potential in reducing neuronal inflammation.

Structure-guided discovery of potent, selective, orally bioavailable, and brain-penetrating RIPK1 inhibitors

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ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.