Identification of a dihydropyridine scaffold that blocks ryanodine receptors

• Published in: iScience Vol. 25; no. 1; p. 103706
• Main Authors: Gunaratne, Gihan S., Rebbeck, Robyn T., McGurran, Lindsey M., Yan, Yasheng, Arzua, Thiago, Frolkis, Talia, Sprague, Daniel J., Bai, Xiaowen, Cornea, Razvan L., Walseth, Timothy F., Marchant, Jonathan S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.01.2022; Elsevier
• Subjects: Biochemistry; Cell biology; Molecular physiology; Natural product chemistry; Cell biology; Biochemistry; Natural product chemistry; Molecular physiology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2021.103706

Ryanodine receptors (RyRs) are large, intracellular ion channels that control Ca2+ release from the sarco/endoplasmic reticulum. Dysregulation of RyRs in skeletal muscle, heart, and brain has been implicated in various muscle pathologies, arrhythmia, heart failure, and Alzheimer's disease. Therefore, there is considerable interest in therapeutically targeting RyRs to normalize Ca2+ homeostasis in scenarios involving RyR dysfunction. Here, a simple invertebrate screening platform was used to discover new chemotypes targeting RyRs. The approach measured Ca2+ signals evoked by cyclic adenosine 5′-diphosphate ribose, a second messenger that sensitizes RyRs. From a 1,534-compound screen, FLI-06 (currently described as a Notch “inhibitor”) was identified as a potent blocker of RyR activity. Two closely related tyrosine kinase inhibitors that stimulate and inhibit Ca2+ release through RyRs were also resolved. Therefore, this simple screen yielded RyR scaffolds tractable for development and revealed an unexpected linkage between RyRs and trafficking events in the early secretory pathway. [Display omitted] •FLI-06 inhibits transport in the secretory pathway via an unknown mechanism•An invertebrate screening platform revealed FLI-06 blocks intracellular Ca2+ release•FLI-06 acts as a potent, cell-permeable ryanodine receptor (RyR) blocker•The para-substituted dihydropyridine chemotype is a new scaffold for RyR modulation Biochemistry; Cell biology; Molecular physiology; Natural product chemistry