生物活性

• 描述CDK4/6, forming a complex with its partner Cyclin D1/2/3, can mediate the phosphorylation of Rb in G1 cell cycle, as well as stimulating the synthesis cyclin E and D-type cyclins controlled by extracellular mitogens^[1]. LEE011 (Ribociclib) is an orally bioavailable dual CDK4/6 inhibitor with IC50 values of 10 nM and 40 nM, respectively^[2]. Treatment of LEE011 (0.25 - 10 μM) can cause decrease in pRB-S780 accompany growth suppression in BE2C, EBC1, IMR5 and SKNAS neuroblastoma cell lines by a dose-dependent manner. 100 - 250nM of LEE011 can cause accumulation of G0/G1 phase of the cell cycle and cellular senescence with decreased FOXM1 in BE2C and IMR5 cells. Treatment of once daily for 21 days with 200mg/kg LEE011 can suppress neuroblastoma growth in mice with subcutaneously implanted BE2C or 1643 xenografts^[3]. There are currently 16 active clinical trials with LEE011 as single agent or in combination with other drugs of treatment for melanoma, breast cancer, neuroblastoma, malignant rhabdoid and lymphomas^[4].
• 作用机制LEE011 can inhibit CDK4/6 in an ATP-competitive manner through its pyrrolo[2,3d]pyrimidine core^[5].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  1643	-	Growth Inhibition Assay	24 h	IC50=147 nM	24045179
  449	-	Growth Inhibition Assay	72 h	inhibits cell growth dose dependently	25028469
  449	3.33 μM	Growth Inhibition Assay	24 h	decreases the proportion of cells in S phase	25028469

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• 动物研究
  剂量	Rat[6] (p.o.): min = 10 mg/kg, max = 300 mg/kg
  给药途径	p.o.
  动物药代数据	Animal Dogs[7] Monkeys[7] Dose 2 mg/kg Administration p.o. T1/2 18 h 4.69 h CL 31 ml/min/kg 35.3 ml/(min·kg) Vd 28 L/kg F 0.64 0.166

• 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
  NCT02813135	Children, Adolescents and Youn... more >>g Adults With Refractory or Recurrent Malignancies Collapse <<	Phase 1 Phase 2	Recruiting	January 2022	France ... more >> Gustave Roussy Recruiting Villejuif, Val De Marne, France, 94805 Contact: Birgit Geoerger, MD    1 42 11 4661 ext +33    birgit.geoerger@gustaveroussy.fr    Contact: Xavier Paoletti, MD    1 42 11 6564 ext +33    xavier.paoletti@gustaveroussy.fr    Principal Investigator: Birgit Geoerger, MD          Germany University Children's Hospitalermany Not yet recruiting Heidelberg, Germany Contact: Olaf Witt, MD    6221 56 4555 ext +49    O.Witt@Dkfz-Heidelberg.de    Italy Fondazione IRCCS Istituto Nazionale dei Tumori Not yet recruiting Milan, Italy Contact: Michela Casanova, MD    02 23 90 25 94 ext +39    Michela.Casanova@istitutotumori.mi.it    Netherlands Erasmus MC, Sophia Children's Hospital Not yet recruiting Rotterdam, Netherlands Contact: Michel Zwaan, MD    10 703 6691 ext +31    c.m.zwaan@erasmusmc.nl    Spain Unidad de Oncología Pediátrica Hospital Niño Jesús Not yet recruiting Madrid, Spain, 28009 Contact: Francisco Bautista, MD    915 035 900 ext +43    franciscojose.bautista@salud.madrid.org    United Kingdom Pediatric and Adolescent Oncology The Royal Marsden Hospital Not yet recruiting Sutton, United Kingdom Contact: Lynley Marshall, MD    208 661 3678 ext +44    Lynley.Marshall@icr.ac.uk Collapse <<
  NCT03280563	Breast Neoplasms	Phase 1 Phase 2	Recruiting	October 7, 2022	-
  NCT03333343	EGFR-mutant Non-small Cell Lun... more >>g Cancer Collapse <<	Phase 1	Recruiting	May 21, 2021	Canada, Ontario ... more >> Novartis Investigative Site Recruiting Toronto, Ontario, Canada, M5G 2M9 Germany Novartis Investigative Site Recruiting Koeln, Germany, 50937 Italy Novartis Investigative Site Recruiting Ancona, AN, Italy, 60126 Novartis Investigative Site Recruiting Milano, MI, Italy, 20162 Singapore Novartis Investigative Site Recruiting Singapore, Singapore, 169610 Taiwan Novartis Investigative Site Recruiting Tainan, Taiwan, 70421 Novartis Investigative Site Recruiting Taipei, Taiwan, 10002 Collapse <<

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• 参考文献

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

  [2] Finn RS, Aleshin A, et al. Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers. Breast Cancer Res. 2016 Feb 9;18(1):17.

  [3] Rader J, Russell MR, et al. Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin Cancer Res. 2013 Nov 15;19(22):6173-82.

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

  [5] Barvian M, Boschelli DH, et al. Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases. J Med Chem. 2000 Nov 30;43(24):4606-16.

  [6] In vivo studies of LEE011

  [7] 209092orig1s000multidiscipliner

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