生物活性

• 靶点

  HDAC1 IC50:1.7nM

  HDAC10 IC50:2.8nM

  HDAC2 IC50:5nM

  HDAC3 IC50:1.8nM

  PI3Kα IC50:19nM

• 描述PI3K pathway plays an important role in cancer cell initiation, growth, proliferation, and survival. HDACs can affect a variety of cell functions, by regulating both histone and nonhistone substrates, and synergize with PI3K. CUDC-907 is a dual inhibitor of both class I/ II HDACs, IC50 of 1.7 nM，5 nM，1.8 nM， 27 nM，2.8 nM and 5.4 nM for HDAC1，HDAC2，HDAC3，HDAC7，HDAC10 and HDAC11 and class I PI3Ks, IC50 of 19 nM, 54 nM, and 39 nM for PI3Ka, PI3Kb, and PI3Kd, respectively. Similar to other pan-HDAC inhibitors, CUDC-907 markedly increased acetylated histones as well as non-histone proteins such as tubulin and p53 and also induced p21 protein expression in H460 cell lines at concentration of 1 μM. As a PI3K inhibitor, CUDC-907 decreased phosphorylation of AKT and its downstream targets, 4EBP-1 and p70S6. Treatment with 1 μM CUDC-907 can induce cell-cycle arrest at G2–M phase and apoptosis, measured by the accumulation of cleaved PARP, activated caspase-7, p21, as well as the reduction of anti-apoptotic proteins including BCL-2, BCL-xL, and survivin in H460 cells. Treatment with CUDC-907 intravenously (50 mg/kg) can cause tumor regression in a xenograft tumor model of SU-DHL4 diffuse large B-cell lymphoma (DLBCL) while oral administration (100 mg/kg) can cause tumor stasis in RAS-mutant A549 NSCLC cell xenografts^[1]. Phase 2 clinical trial of CUDC-907 for treatment of relapsed and/or refractory diffuse large B-cell lymphoma including with Myc alterations and prostate cancer are undergoing (see in https://clinicaltrials.gov/).
• 作用机制CUDC-907 has the hydroxamic acid, which can chelate Zn²⁺ ion of HDAC, and the morpholinopyrimidine, a core structure scaffold shared by several PI3K inhibitors.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  human Glioma cells (HF2303)	-	Cytotoxicity assay	72 h	Cytotoxicity against human Glioma cells (HF2303) after 72 hrs by CelltiterGlo assay, EC50=0.7 nM	26288699
  human Glioma cells (HF2381)	-	Cytotoxicity assay	72 h	Cytotoxicity against human Glioma cells (HF2381) after 72 hrs by CelltiterGlo assay, EC50=0.7 nM	26288699
  human Glioma cells (HF2476)	-	Cytotoxicity assay	72 h	Cytotoxicity against human Glioma cells (HF2476) after 72 hrs by CelltiterGlo assay, EC50=0.7 nM	26288699

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• 动物研究
  剂量	Mice[1]: 25 mg/kg (i.v.), 100 mg/kg (p.o.)
  给药途径	i.v., p.o.
  动物药代数据	Animal Nude mice[1] Dose 100 mg/kg Administration p.o. T1/2 7.7 h (plasma) 12.6 h (tumor tissue)

• 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
  NCT02913131	Prostate Cancer	Phase 2	Recruiting	April 2020	United States, California ... more >> University of California, San Francisco Recruiting San Francisco, California, United States, 94158 Contact: Rahul Aggarwal, MD    877-827-3222    cancertrials@ucsf.edu    Contact: Kamran Abri-Lavasani    877-827-3222    cancertrials@ucsf.edu Collapse <<
  NCT01742988	Multiple Myeloma ... more >> Lymphoma Collapse <<	Phase 1	Active, not recruiting	December 2018	United States, California ... more >> USC/Norris Comprehensive Cancer Center Los Angeles, California, United States, 90033 United States, Florida Florida Cancer Specialists Sarasota, Florida, United States, 34232 United States, New York Memorial Sloan-Kettering Cancer Center New York, New York, United States, 10065 United States, Oklahoma Stephenson Cancer Center, University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma, United States, 73104 United States, Tennessee Sarah Cannon Research Institute Nashville, Tennessee, United States, 37203 United States, Texas MD Anderson Cancer Center Houston, Texas, United States, 77030 Collapse <<
  NCT03002623	Thyroid Neoplasms ... more >> Poorly Differentiated and Undifferentiated Thyroid Cancer Differentiated Thyroid Cancer Collapse <<	Phase 2	Completed	-	United States, Maryland ... more >> National Institutes of Health Clinical Center Bethesda, Maryland, United States, 20892 Collapse <<

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• 参考文献

• [1] Qian C, Lai CJ, et al. Cancer network disruption by a single molecule inhibitor targeting both histone deacetylase activity and phosphatidylinositol 3-kinase signaling. Clin Cancer Res. 2012 Aug 1;18(15):4104-13.