生物活性

• 靶点

  CDK4 IC50:2nM

  Cdk6 IC50:10nM

• 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]. LY2835219 (abemaciclib) can selectively inhibit CDK4/cyclin D1 and CDK6/cyclin D1 with IC50 values of 2 nM and 10 nM (measured by enzymatic assays), respectively. Treatment with LY2835219 for 24h showed a dose-dependent inhibition of pRb-S780, with IC50 of 120 nM, and G1 arrest with EC50 of 72 nM in Colo-205 colorectal cells. Similar effect can also be observed in MCF10A and MV4-11 AML cells. LY2835219 showed the good pharmacodynamics. Oral dose>12.5 mg/kg for 24h can decrease the level of p-Rb (a phenotypic marker for cells in G1 and CDK4/6 inhibition), topisomerase II alpha (a marker for cells in S phase) and pHH3 (a marker for cells in M phase) in mice bearing colo-205 human xenografts. Oral treatment of LY2835219 on dose of 25 - 100 mg/kg for 21 days significantly inhibited the growth of colo-205 and MV4-11 xenograft mice^[2]. There are 10 ongoing clinical trials using LY2835219 as a single agent or in combination for the treatment of tumors including breast, lung cancer, lymphoma and MCL, Stage IV NSCLC with a detectable KRAS mutation and breast cancer^[3].
• 作用机制LY2835219 is a competitive ATP CDK4/6 inhibitor^[2].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  human COLO205 cells	-	Function assay	24 h	Inhibition of CDK4/6 in human COLO205 cells assessed as inhibition of Rb phosphorylation after 24 hrs by propidium iodide staining-based laser-scanning fluorescence microplate cytometric analysis	26115571
  human COLO205 cells	-	Function assay	24 h	Inhibition of CDK4/6 in human COLO205 cells assessed as maximum cell cycle arrest at G1 phase after 24 hrs by propidium iodide staining-based flow cytometric analysis	26115571
  insect cells	-	Function assay	50 mins	Competitive inhibition of human CDK4/cyclin D1 expressed in insect cells assessed as phosphorylation of CTRF after 50 mins by Michaelis-Menten plot analysis in presence of ATP, Ki=0.6 nM	26115571

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• 动物研究
  剂量	Mice[4] (s.c.): min = 12.5 mg/kg, max = 100 mg/kg
  给药途径	s.c.
  动物药代数据	Animal Rats[5] Dose 40 mg/kg Administration o.p. Cmax 789 ng/ml T1/2 10.3 h AUC0-48h 22000 F 0.595

• 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
  NCT03732703	Relapsed Refractory Multiple M... more >>yeloma Collapse <<	Phase 1 Phase 2	Not yet recruiting	February 10, 2024	United States, Arizona ... more >> Mayo Clinic - Arizona Not yet recruiting Phoenix, Arizona, United States, 85054 United States, California City of Hope Not yet recruiting Duarte, California, United States, 91010 United States, Georgia Emory University Not yet recruiting Atlanta, Georgia, United States, 30322 United States, Massachusetts Massachusetts General Hospital Cancer Center Not yet recruiting Boston, Massachusetts, United States, 02114 Beth Israel Deaconess Not yet recruiting Boston, Massachusetts, United States, 02215 Dana Farber Cancer Institute Not yet recruiting Boston, Massachusetts, United States, 02215 United States, Michigan University of Michigan Health System Not yet recruiting Ann Arbor, Michigan, United States, 48109 Karmanos Cancer Center Not yet recruiting Detroit, Michigan, United States, 48201 United States, Minnesota Mayo Clinic - Minnesota Not yet recruiting Rochester, Minnesota, United States, 55905 United States, Missouri Washington University School of Medicine Division of Medical Oncology Not yet recruiting Saint Louis, Missouri, United States, 63110 United States, New Jersey Hackensack University Medical Center Not yet recruiting Hackensack, New Jersey, United States, 07610 United States, New York Mount Sinai School of Medicine Not yet recruiting New York, New York, United States, 10029 Memorial Sloan Kettering Cancer Center Not yet recruiting New York, New York, United States, 10065 United States, North Carolina Levine Cancer Institute Not yet recruiting Charlotte, North Carolina, United States, 28204 United States, Ohio Ohio State University College of Medicine Not yet recruiting Columbus, Ohio, United States, 43210 United States, Texas UT Southwestern Medical Center Not yet recruiting Dallas, Texas, United States, 75390 United States, Virginia Virginia Cancer Specialists Not yet recruiting Fairfax, Virginia, United States, 22031 Collapse <<
  NCT02745769	Advanced Cancer ... more >> Colorectal Cancer Mantle Cell Lymphoma Collapse <<	Phase 1	Active, not recruiting	May 1, 2019	United States, Alabama ... more >> UAB Comprehensive Cancer Center Birmingham, Alabama, United States, 35249 United States, Texas University of Texas MD Anderson Cancer Center Houston, Texas, United States, 77030 France For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Lyon, France, 69373 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Marseille, France, 13385 United Kingdom For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. London, United Kingdom, SE1 9RT Collapse <<
  NCT03654833	Mesothelioma, Malignant	Phase 2	Not yet recruiting	November 30, 2021	-

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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] , et al. Symposium on the use of sinusoidally modulated light for the study of visual mechanisms in normal subjects, patients and animals (dogs). Electroencephalogr Clin Neurophysiol. 1967 Dec;23(6):586-7.

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

  [4] Gelbert LM, Cai S, et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs. 2014 Oct;32(5):825-37.

  [5] 208716Orig1s000MultidisciplineR

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