生物活性

• 靶点

  CDK1 IC50:~40nM

  CDK2 IC50:~40nM

  CDK4 IC50:~40nM

  Cdk6 IC50:~40nM

• 描述Flavopiridol 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^[1][2].
  
  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^[3].
  
  Intraperitoneal treatment of 5mg/kg flavopiridol for 12 days showed antitumor activity in subcutaneous HN12 xenograft mice^[4].
  
  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^[5].
• 作用机制Flavopiridol is an ATP-competitive inhibitor^[6].
• 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: min = 5 mg/kg, max = 7.5 mg/kg[6]
  给药途径	i.p.
  动物药代数据	Animal Mice AUC0→∞ 1.6 h (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
  NCT03604783	Advanced Solid Tumors	Phase 1	Not yet recruiting	May 2021	United States, Wisconsin ... more >> Medical College of Wisconsin Not yet recruiting Milwaukee, Wisconsin, United States, 53226 Contact: Katy C Schroeder, BSN, RN, OCN    414-805-8843       Principal Investigator: Ben George, MD Collapse <<
  NCT00055380	Cancer	Phase 1	Completed	-	United States, Maryland ... more >> National Institute of Dental And Craniofacial Research (NIDCR) Bethesda, Maryland, United States, 20892 Collapse <<
  NCT00003004	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 <<

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• 参考文献

• [1] Montagnoli A, Valsasina B, et al. A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity. Nat Chem Biol. 2008 Jun;4(6):357-65.

  [2] Aleem E, Arceci RJ, et al. Targeting cell cycle regulators in hematologic malignancies. Front Cell Dev Biol. 2015 Apr 9;3:16.

  [3] Sedlacek HH, et al. Mechanisms of action of flavopiridol. Crit Rev Oncol Hematol. 2001 May;38(2):139-70.

  [4] Roskoski R Jr, et al. Cyclin-dependent protein kinase inhibitors including palbociclib as anticancer drugs. Pharmacol Res. 2016 May;107:249-275.

  [5] Li Y, Zhang J, et al. Insights on Structural Characteristics and Ligand Binding Mechanisms of CDK2. Int J Mol Sci. 2015 Apr 24;16(5):9314-40.

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