生物活性

• 靶点

  CDK1 IC50:~40nM

  CDK2 IC50:~40nM

  CDK4 IC50:~40nM

  Cdk6 IC50:~40nM

• 描述Flavopiridol Hydrochloride is the hydrochloride form of Flavopiridol. Flavopiridol (Alvocidib) is a pan CDK inhibitor with IC50 value of 30nM, 40nM, 20-40nM, 60nM, 875nM and 20nM for CDK1, 2, 4, 6, 7, 9 (measured by in vitro kinase assays), respectively. It can inhibit the whole cell cycle progression through a variety of mechanisms related to CDK inactivation including: 1. Inhibition of CDK4/6 with cyclin D leads to decreased level of pRb-p107 and p130, as well as inactivation of E2F and stop in G1 progression; 2. Inhibition of cdk2 accompanied with cyclin A or E leads to further decreased phosphorylation and inactivation of Rb, as well as inactivation of E2F, and results in retardation in cell cycle progression through the S-phase and accumulation in G1 and G2; 3. Inhibition of CDK1 accompanied with cyclin A or B leads to inhibition of activation of topoisomerase activators, of lamin proteoglycans histone 1 protein and chromatin condensation, as well as results in retardation in cell cycle progression through S-phase and accumulation in G2 phase; 4. Inhibition of cdk7 accompanied with cyclin H complexes leads to reduced activation of cdk's, such as CDK4 with cyclin D or CDK1 with cyclin B, and reduced activation of RNA polymerase; 5. Flavopiridol may directly influence expression of cyclin D1 and D3 or participate directly in the control of transcription and activation of RNA-polymerase. Flavopiridol is able to induce apoptosis of tumor cells, including leukemia cells, head and neck tumors, breast carcinomas and non-small cell lung carcinoma cell lines, as well as normal cells in vitro after 6–48h with concentration ranging in 0.1–0.4uM. Intraperitoneal treatment of 5mg/kg flavopiridol for 12 days showed antitumor activity in subcutaneous HN12 xenograft mice. Clinical studies of flavopiridol of treatement for advanced solid tumors, ALL, AML, CLL, CML, mantle cell lymphoma, multiple myeloma, non-Hodgkin and other lymphomas, advanced sarcomas, breast, esophageal, head and neck, kidney, ovarian, pancreatic, gastric carcinomas and NSCLC are undergoing.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  A2780 cell	-	Function assay	-	Inhibition of A2780 cell clonogenic assay， IC50=15 μM	11063609
  A2780/DDP-R human ovarian carcinoma cell	-	Proliferation assay	-	Inhibition of A2780/DDP-R human ovarian carcinoma cell proliferation, IC50=38 nM	12190313
  A2780/DDP-S human ovarian carcinoma cell	-	Proliferation assay	-	Inhibition of A2780/DDP-S human ovarian carcinoma cell proliferation, IC50=56 nM	12190313

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• 动物研究
  剂量	Mice: 5 mg/kg, 7.5 mg/kg[3] (i.p.) Rat: 0.01 mg/kg- 5 mg/kg[4] (i.p.)
  给药途径	i.p.

• 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
  NCT02520011	Acute Myeloid Leukemia	Phase 2	Recruiting	December 2019	-
  NCT00006485	Unspecified Adult Solid Tumor,... more >> Protocol Specific Collapse <<	Phase 1	Completed	-	United States, New York ... more >> Memorial Sloan-Kettering Cancer Center New York, New York, United States, 10021 Collapse <<
  NCT00087282	Liver Cancer	Phase 2	Completed	-	United States, New York ... more >> Memorial Sloan-Kettering Cancer Center New York, New York, United States, 10021 Collapse <<

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• 参考文献

• [1] Senderowicz AM. The cell cycle as a target for cancer therapy: basic and clinical findings with the small molecule inhibitors flavopiridol and UCN-01. Oncologist. 2002;7 Suppl 3:12-9.

  [2] Carlson BA, Dubay MM, et al. Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Cancer Res. 1996 Jul 1;56(13):2973-8.