9F0A

N5 Adduct of LSD1-CoREST in complex with MC4455

This is a non-PDB format compatible entry.

Summary for 9F0A

• Entry DOI: 10.2210/pdb9f0a/pdb
• Descriptor: Lysine-specific histone demethylase 1A, REST corepressor 1, [[(2~{S},3~{R},4~{S},5~{S})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(2~{S},3~{S},4~{R})-5-[5-[3-[4-[[4-[[(2~{S})-3-(3,4-dihydro-1~{H}-isoquinolin-2-yl)-2-oxidanyl-propyl]carbamoyl]pyridin-2-yl]amino]phenyl]propanoyl]-7,8-dimethyl-2,4-bis(oxidanylidene)-4~{a}~{H}-benzo[g]pteridin-10-yl]-2,3,4-tris(oxidanyl)pentyl] hydrogen phosphate (3 entities in total)
• Functional Keywords: protein complex, epigenetics, inhibitor, flavoprotein, transcription, oxidoreductase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 102768.36

Authors

Barone, M.,Mattevi, A. (deposition date: 2024-04-15, release date: 2025-04-23, Last modification date: 2026-05-06)

Primary citation

Param, N.J.,Arceci, E.,Fiorentino, F.,Pignata, L.,Torre, D.,Gutierrez-Trejo, N.,Fong, J.Y.,Goy, P.A.,Han, B.Y.,Lambona, C.,Di Bello, E.,Castiello, C.,Barone, M.,Schwarz, M.,Arrowsmith, C.,Ito, K.,Scherle, P.,Wee, D.K.B.,Ndoye, S.,Tabaglio, T.,Jeyasekharan, A.D.,Lakshmanan, M.,Cirilli, R.,Habisch, H.,Madl, T.,Mattevi, A.,Valente, S.,Mai, A.,Guccione, E.
A synergistic interaction between PRMT5 and LSD1 inhibitors in AML.
Sci Adv, 12:eaea4059-eaea4059, 2026

PubMed Abstract: Acute myeloid leukemia (AML) is a hematopoietic malignancy caused by abnormal proliferation and differentiation of blasts. PRMT5, a methyltransferase that catalyzes symmetric dimethylation of arginine (SDMA) residues, has been implicated in cancer stem cell homeostasis and shown to be a potential therapeutic target in AML. However, given the toxicity of complete PRMT5 inhibition, there is a need to identify effective synergistic therapies. Through a targeted screen of compounds that inhibit key nodes of PRMT5-regulated pathways, we identified a synthetic lethality between inhibition of PRMT5 and LSD1, a lysine demethylase known to affect AML blast differentiation. The two inhibitors broadly reshape the transcriptome of targeted cells and synergize to promote AML differentiation and eventually growth inhibition and apoptosis, in a p53-dependent manner. To leverage this synthetic lethal interaction, we generated new dual compounds to inhibit both enzymes and recapitulated the effects of the drug combination. Our results uncover an unexpected convergence of PRMT5- and LSD1-regulated targets, paving the way for new therapeutic opportunities.

PubMed: 41894488
DOI: 10.1126/sciadv.aea4059

Experimental method

X-RAY DIFFRACTION (3.36 Å)