生物活性

• 靶点	Bromodomain CREBBP IC50:3μM

• 描述CBP has acetyltransferase activity and affects cell proliferation and differentiation. CBP and the closely related p300 are recruited Wnt-responsive promotes through interactions with the C-terminal half of β-catenin. PRI 724 is a novel inhibitor for Wnt/β-catenin/CBP pathway with IC50 value of 150nM^[1]. In vitro, PRI 724 exhibited concentration dependent cytotoxicity in concentration range of 5-100μM to head and neck carcinoma lines BICR6, UM-SCC-1, and oral keratinocyte cell lines CAL27, FaDu, H314, SCC-25, OKF4/TERT-1. PRI 724 also reduced the transcript level of Wnt target genes Axin2, MMP7, and BIRC5 in these cells. Treatment with 20μM PRI 724 showed ability to inhibit the migration of BICR6, CAL27, FaDu and SCC-25 cells. In addition, PRI 724 reduced the percentage of G0/G1 cells in CAL27, SCC-25 and UM-SCC-1 cell lines, but slightly increased the percentage of G0/G1 cells in the FaDu cell linePMID: 31089983. In vivo, administration of 30mg/kg PRI 724 once daily significantly improved the overall survival of the leukemia-bearing NSG mice^[2]. Subcutaneous administration of 10mg/kg PRI 724 once daily for 5 days ameliorated bleomycin-induced pulmonary fibrosis in mice^[3].
• 作用机制PRI 724 specifically disruption the interaction of CBP and β-catenin to inhibit Wnt/β-catenin/ CBP signaling pathway^[3].
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02413853	Colorectal Adenocarcinoma ... more >> Stage IVA Colorectal Cancer Stage IVB Colorectal Cancer Collapse <<	Phase 2	Withdrawn(Study drug supply is... more >>sues) Collapse <<	November 2018	United States, California ... more >> USC Norris Comprehensive Cancer Center Los Angeles, California, United States, 90033 Collapse <<
  NCT01606579	Acute Myeloid Leukemia ... more >> Chronic Myeloid Leukemia Collapse <<	Phase 1 Phase 2	Completed	-	United States, Georgia ... more >> Emory University / Winship Cancer Institute Atlanta, Georgia, United States, 30322 United States, Massachusetts University of Massachusetts Medical Center Worcester, Massachusetts, United States, 01655 United States, New Mexico New Mexico Cancer Care Alliance Albuquerque, New Mexico, United States, 87106 United States, North Carolina Duke University Medical Center Durham, North Carolina, United States, 27710 United States, Ohio Ohio State University Columbus, Ohio, United States, 43210-1267 United States, Texas University of Texas M.D. Anderson Cancer Center Houston, Texas, United States, 77030 Collapse <<
  NCT02828254	-	-	Completed	-	Japan ... more >> Tokyo metropolitan Komagome Hospital Tokyo, Japan Collapse <<

• 更多
• 参考文献

• [1] Feng C. Lysophosphatidylcholine acyltransferase 3 deficiency impairs 3T3L1 cell adipogenesis through activating Wnt/β-catenin pathway. Biochim Biophys Acta Mol Cell Biol Lipids. 2018 Aug;1863(8):834-843. doi: 10.1016/j.bbalip.2018.04.008. Epub 2018 Apr 17.

  [2] Zhou H. Combined inhibition of β-catenin and Bcr-Abl synergistically targets tyrosine kinase inhibitor-resistant blast crisis chronic myeloid leukemia blasts and progenitors in vitro and in vivo. Leukemia. 2017 Oct;31(10):2065-2074. doi: 10.1038/leu.2017.87. Epub 2017 Mar 21.

  [3] Okazaki H. The novel inhibitor PRI-724 for Wnt/β-catenin/CBP signaling ameliorates bleomycin-induced pulmonary fibrosis in mice. Exp Lung Res. 2019 Sep;45(7):188-199. doi: 10.1080/01902148.2019.1638466.