7WWZ

BRD4-BD1 complexed with NEO2734

Summary for 7WWZ

• Entry DOI: 10.2210/pdb7wwz/pdb
• Descriptor: Isoform C of Bromodomain-containing protein 4, 1,3-dimethyl-5-[2-(oxan-4-yl)-3-[2-(trifluoromethyloxy)ethyl]benzimidazol-5-yl]pyridin-2-one (3 entities in total)
• Functional Keywords: brd4, bromodomain, neo2734, complex, structural protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 15403.62

Authors

Zeng, L.,Lei, J.D. (deposition date: 2022-02-14, release date: 2022-06-08, Last modification date: 2023-11-29)

Primary citation

Ji, D.,Shang, G.,Wei, E.,Jia, Y.,Wang, C.,Zhang, Q.,Zeng, L.
Targeting CDCP1 gene transcription coactivated by BRD4 and CBP/p300 in castration-resistant prostate cancer.
Oncogene, 41:3251-3262, 2022

PubMed Abstract: CUB domain-containing protein 1 (CDCP1), a transmembrane protein with tumor pro-metastatic activity, is highly expressed in late-stage and castrate-resistant prostate cancer (CRPC). However, the molecular mechanism driving CDCP1 overexpression in CRPC progress remains elusive. Here we report that transcription cofactors BRD4 and CBP/p300 co-regulate transcriptional expression of CDCP1 in CRPC tumorigenesis. In contrast to androgen receptor (AR) in CRPC, increased expression of BRD4 and CBP/p300 is strongly correlated with CDCP1 gene amplification. Combined knockdown or dual-inhibition of BRD4 and CBP/p300 down-regulated CDCP1 transcription and downstream PI3K/AKT and/or SRC/MAPK signaling pathways in CRPC cells much more so than single-protein perturbation. Our biochemical and structural analyses further showed that NEO2734, a dual-inhibitor targeting BRD4 and p300 bromodomains exhibits greater efficacy than single inhibitors for BRD4 or CBP/p300 in suppressing CDCP1 transcriptional expression and its downstream signaling pathways in CRPC cell proliferation and metastasis. Our study illustrates that targeting CDCP1 through dual-inhibition of BRD4 and CBP/p300 represents a synergistic therapeutic strategy for new treatment of CRPC.

PubMed: 35513563
DOI: 10.1038/s41388-022-02327-5

Experimental method

X-RAY DIFFRACTION (1.16 Å)