7usi | pdb_00007usi

BRD2-BD1 in complex with MDP5

spinqualitylabelsall models 7usi, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7usi is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CL, DMS, EDO, NA, O6O, PEG, PGE Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function BRD2_HUMAN May play a role in spermatogenesis or folliculogenesis (By similarity). Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling. Regulates transcription of the CCND1 gene. Plays a role in nucleosome assembly. Publication Abstract from PubMed Medulloblastoma (MB) is a malignant pediatric brain tumor which shows upregulation of MYC and sonic hedgehog (SHH) signaling. SHH inhibitors face acquired resistance, which is a major cause of relapse. Further, direct MYC oncogene inhibition is challenging, inhibition of MYC upstream insulin-like growth factor/ phosphatidylinositol-4,5-bisphosphate 3-kinase (IGF/PI3K) is a promising alternative. While PI3K inhibition activates resistance mechanisms, simultaneous inhibition of bromodomain-containing protein 4 (BRD4) and PI3K can overcome resistance. We synthesized a new molecule 8-(2,3-dihydrobenzo[b] [1, 4] dioxin-6-yl)-2-morpholino-4H-chromen-4-one (MDP5) that targets both BRD4 and PI3K pathways. We used X-ray crystal structures and a molecular modeling approach to confirm the interactions between MDP5 with bromo domains (BDs) from both BRD2 and BRD4, and molecular modeling for PI3K binding. MDP5 was shown to inhibit target pathways and MB cell growth in vitro and in vivo. MDP5 showed higher potency in DAOY cells (IC(50) 5.5 muM) compared to SF2523 (IC(50) 12.6 muM), and its IC(50) values in HD-MB03 cells were like SF2523. Treatment of MB cells with MDP5 significantly decreased colony formation, increased apoptosis, and halted cell cycle progression. Further, MDP5 was well tolerated in NSG mice bearing either xenograft or orthotopic MB tumors at the dose of 20 mg/kg, and significantly reduced tumor growth and prolonged animal survival. Targeting BRD4 and PI3K signaling pathways for the treatment of medulloblastoma.,Sethi B, Kumar V, Jayasinghe TD, Dong Y, Ronning DR, Zhong HA, Coulter DW, Mahato RI J Control Release. 2023 Jan 5;354:80-90. doi: 10.1016/j.jconrel.2022.12.055. PMID:36599397 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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