28zs | pdb_000028zs
Crystal structure of human DHX8 in complex with compound 53 and ADP
Structural highlights
FunctionDHX8_HUMAN Facilitates nuclear export of spliced mRNA by releasing the RNA from the spliceosome.[1] GST26_SCHJA Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. GST isoenzymes appear to play a central role in the parasite detoxification system. Other functions are also suspected including a role in increasing the solubility of haematin in the parasite gut. Publication Abstract from PubMedHuman DHX8 is a spliceosomal DEAH-box RNA helicase involved in releasing mRNA from the spliceosome and crucial in ensuring splicing fidelity. DHX8 was identified as a promising therapeutic oncology target due to its role in regulating stress-adaptive gene expression, including HSF1-dependent transcription, while having broader transcriptional effects in cells under oncogenic stress. We report the discovery of novel RNA-competitive DHX8 inhibitors based on a 2-(phenethylthio)nicotinic acid scaffold, which were optimized using a structure-guided design approach, following a biophysical fragment screen. This yielded compound 53 with nanomolar biochemical potency, good in vitro PK, and activity in a cellular target engagement assay. Optimizing inhibitor binding between Arg647 and the nonconserved His693, coupled with extending into a pocket in the DHX8 Winged-Helix domain, was crucial for potency improvement. By binding in the Winged-Helix domain, these inhibitors restrict the helicase domain's conformational plasticity, stabilizing a closed, inactive conformation while sterically blocking ssRNA translocation. Fragment-Based Discovery of Potent RNA-Competitive Inhibitors of the DEAH-Box RNA Helicase DHX8.,Read BJ, Ewens C, Gigante F, Thomas J, Felisberto-Rodrigues C, Alvarez Peres S, Tighe C, de Las Heras Ruiz E, Schiemann K, Malcolm AG, McAndrew PC, Stubbs M, Patani H, Costa HDS, Stoodley K, Pickard L, Busch M, Gunnell E, Silva S, Knopp A, Hallett ST, Augustin M, Lammens A, Carter M, Meniconi M, Ballarotto M, Ainsley J, Meister P, Sethi D, Burke R, Scarpino A, Le Bihan YV, Gradler U, Blagg J, Workman P, Clarke PA, Blum A, Esdar C, Bhalay G, van Montfort RLM J Med Chem. 2026 Aug 13;69(15):18277-18299. doi: 10.1021/acs.jmedchem.6c00732. PMID:42593941[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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