生物活性

• 靶点

  Cdk6 IC50:10nM

  CDK4 IC50:2nM

• 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. LY2835219 (abemaciclib) can selectively inhibit CDK4/cyclin D1 and CDK6/cyclin D1 with IC50 value of 2nM and 10nM (measured by enzymatic assays), respectively. Treatment with LY2835219 for 24h showed a dose-dependent inhibition of pRb-S780, with IC50 of 120nM, and G1 arrest with EC50 of 72nM 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>12.5mg/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. Orally treatment of LY2835219 on dose of 25-100mg/kg for 21 days significantly inhibited the growth of colo-205 and MV4-11 xenografts mice. 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.
• 作用机制LY2835219 is a competitive ATP CDK4/6 inhibitor.
• 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
  NCT01655225	Advanced Cancer ... more >> Metastatic Cancer Non-Hodgkin's Lymphoma Metastatic Breast Cancer Malignant Mesothelioma Non-small Cell Lung Cancer Collapse <<	Phase 1	Recruiting	March 1, 2021	United States, California ... more >> UCLA Medical Center Recruiting Los Angeles, California, United States, 90095 Contact    3103258252       Principal Investigator: Parvin Fatheddin Peddi          United States, New York Memorial Sloan Kettering Cancer Center Recruiting New York, New York, United States, 10065 Contact    646-888-4226       Principal Investigator: Anna M Varghese          United States, Oklahoma Peggy and Charles Stephenson Oklahoma Cancer Center Recruiting Oklahoma City, Oklahoma, United States, 73104 Contact    4052718777       Principal Investigator: Raid M D Aljumaily          United States, Pennsylvania Penn Presbyterian Medical Center Completed Philadelphia, Pennsylvania, United States, 19104 United States, Tennessee Sarah Cannon Cancer Center Recruiting Nashville, Tennessee, United States, 37203 Contact    615-239-7615       Principal Investigator: SMO Sarah Cannon Research Inst.          Tennessee Oncology PLLC Recruiting Nashville, Tennessee, United States, 37203 Contact    6153297274       Principal Investigator: Johanna Chock Bendell          Italy Azienda Ospedaliero - Universitaria S. Luigi Gonzaga Completed Orbassano, Torino, Italy, 10043 Puerto Rico Fundacion de Investigacion de Diego Recruiting San Juan, Puerto Rico, 00927 Contact    7877221248       Principal Investigator: Mirelis Acosta-Rivera Collapse <<
  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 <<
  NCT02784795	Solid Tumor B... more >>reast Cancer Colon Cancer Cholangiocarcinoma Soft Tissue Sarcoma Collapse <<	Phase 1	Active, not recruiting	January 31, 2019	United States, Florida ... more >> Sylvester Comprehensive Cancer Center Miami, Florida, United States, 33136 United States, Michigan Karmanos Cancer Institute Detroit, Michigan, United States, 48201 United States, New York Memorial Sloan Kettering Cancer Center New York, New York, United States, 10065 United States, Texas University of Texas MD Anderson Cancer Center Houston, Texas, United States, 77030 Denmark Rigshospitalet Copenhagen, København Ø, Denmark, 2100 France Institut Bergonie Bordeaux, France, 33076 Centre Leon Berard Lyon Cedex 08, France, 69373 Gustave Roussy Villejuif Cedex, France, 94805 Spain Hospital Universitari Vall d'Hebron Barcelona, Spain, 08035 Fundacion Jimenez Diaz Madrid, Spain, 28040 Hospital Madrid Norte Sanchinarro Madrid, Spain, 28050 Collapse <<

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• 参考文献

• [1] Ku BM, Yi SY, et al. The CDK4/6 inhibitor LY2835219 has potent activity in combination with mTOR inhibitor in head and neck squamous cell carcinoma. Oncotarget. 2016 Mar 22;7(12):14803-13.

  [2] Yadav V, Burke TF, et al. The CDK4/6 inhibitor LY2835219 overcomes vemurafenib resistance resulting from MAPK reactivation and cyclin D1 upregulation. Mol Cancer Ther. 2014 Oct;13(10):2253-63.