Identification of ritanserin analogs that display DGK isoform specificity

Ritanserin suppresses acute myeloid leukemia by inhibiting DGKα to downregulate phospholipase D and the Jak-Stat/MAPK pathway

“…The discovery of ritanserin as a DGKα inhibitor highlights the value of repurposing medications, as previous clinical trial data established its safety and tolerability in human subjects [ 30 ]. Studies have shown that ritanserin inhibits C-RAF to cause apoptosis in lung cancer cells and prevents glioblastoma multiforme (GBM) and pancreatic cancer spread by modifying DGKα, which promotes the mesenchymal phenotype [ 10 , 12 ].…”

Predicting small molecule binding pockets on diacylglycerol kinases using chemoproteomics and AlphaFold

“…33 The TH211 probe contains a sulfonyl-triazole electrophile (SuTEx 34 ) that reacts with tyrosine and lysine sites when directed to DGK active sites with the kinase binding element RF001 derived from the DGK inhibitor ritanserin. 35–38 The prominent TH211 binding to the C1 domain of DGKα in T cells coupled with impaired biochemical activity when TH211-modified C1 sites are mutated support potential allosteric regulation through this domain. Whether probe binding to C1 domains of other DGK members occurs in cellular environments, which would support a more general as opposed to DGKα-specific regulatory mechanism, is currently unknown.…”

Discovery of Potent, Dual-Inhibitors of Diacylglycerol Kinases Alpha and Zeta Guided by Phenotypic Optimization

“…Accordingly, it seems unlikely that given an α-selective inhibitor, one would expect to design in ζ inhibition. To the best of our knowledge, these compounds are the first inhibitors targeting both DGKα and ζ. − Due to the lack of structural information, we are unable to speculate on the mechanism of dual inhibition. , Regardless, we have successfully selected for compounds with a unique and desirable profile that represents significant progress in the field of DGK inhibition.…”