دورية أكاديمية
أعرض في EDS

Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine.

التفاصيل البيبلوغرافية
العنوان: Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine.
المؤلفون: Gelbert LM; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA, de_dios_alfonso@lilly.com., Cai S, Lin X, Sanchez-Martinez C, Del Prado M, Lallena MJ, Torres R, Ajamie RT, Wishart GN, Flack RS, Neubauer BL, Young J, Chan EM, Iversen P, Cronier D, Kreklau E, de Dios A
المصدر: Investigational new drugs [Invest New Drugs] 2014 Oct; Vol. 32 (5), pp. 825-37. Date of Electronic Publication: 2014 Jun 13.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Springer Country of Publication: United States NLM ID: 8309330 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1573-0646 (Electronic) Linking ISSN: 01676997 NLM ISO Abbreviation: Invest New Drugs Subsets: MEDLINE
أسماء مطبوعة: Publication: New York : Springer
Original Publication: Boston : M. Nijhoff, 1983-
مواضيع طبية MeSH: Aminopyridines/*pharmacology , Antineoplastic Agents/*pharmacology , Benzimidazoles/*pharmacology , Cyclin-Dependent Kinase 4/*antagonists & inhibitors , Cyclin-Dependent Kinase 6/*antagonists & inhibitors , Protein Kinase Inhibitors/*pharmacology, Aminopyridines/therapeutic use ; Animals ; Antineoplastic Agents/therapeutic use ; Benzimidazoles/therapeutic use ; Cell Line, Tumor ; Deoxycytidine/analogs & derivatives ; Deoxycytidine/pharmacology ; Deoxycytidine/therapeutic use ; Drug Therapy, Combination ; Female ; G1 Phase Cell Cycle Checkpoints/drug effects ; Humans ; Mice ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Neoplasms/pathology ; Phosphorylation/drug effects ; Protein Kinase Inhibitors/therapeutic use ; Retinoblastoma Protein/antagonists & inhibitors ; Retinoblastoma Protein/metabolism ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays ; Gemcitabine
مستخلص: The G1 restriction point is critical for regulating the cell cycle and is controlled by the Rb pathway (CDK4/6-cyclin D1-Rb-p16/ink4a). This pathway is important because of its inactivation in a majority of human tumors. Transition through the restriction point requires phosphorylation of retinoblastoma protein (Rb) by CDK4/6, which are highly validated cancer drug targets. We present the identification and characterization of a potent CDK4/6 inhibitor, LY2835219. LY2835219 inhibits CDK4 and CDK6 with low nanomolar potency, inhibits Rb phosphorylation resulting in a G1 arrest and inhibition of proliferation, and its activity is specific for Rb-proficient cells. In vivo target inhibition studies show LY2835219 is a potent inhibitor of Rb phosphorylation, induces a complete cell cycle arrest and suppresses expression of several Rb-E2F-regulated proteins 24 hours after a single dose. Oral administration of LY2835219 inhibits tumor growth in human tumor xenografts representing different histologies in tumor-bearing mice. LY2835219 is effective and well tolerated when administered up to 56 days in immunodeficient mice without significant loss of body weight or tumor outgrowth. In calu-6 xenografts, LY2835219 in combination with gemcitabine enhanced in vivo antitumor activity without a G1 cell cycle arrest, but was associated with a reduction of ribonucleotide reductase expression. These results suggest LY2835219 may be used alone or in combination with standard-of-care cytotoxic therapy. In summary, we have identified a potent, orally active small-molecule inhibitor of CDK4/6 that is active in xenograft tumors. LY2835219 is currently in clinical development.
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سلسلة جزيئية: ClinicalTrials.gov NCT01394016; NCT01739309; NCT02014129; NCT02057133; NCT02079636; NCT02117648
المشرفين على المادة: 0 (Aminopyridines)
0 (Antineoplastic Agents)
0 (Benzimidazoles)
0 (Protein Kinase Inhibitors)
0 (Retinoblastoma Protein)
0W860991D6 (Deoxycytidine)
60UAB198HK (abemaciclib)
EC 2.7.11.22 (Cyclin-Dependent Kinase 4)
EC 2.7.11.22 (Cyclin-Dependent Kinase 6)
0 (Gemcitabine)
تواريخ الأحداث: Date Created: 20140613 Date Completed: 20150609 Latest Revision: 20221207
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC4169866
DOI: 10.1007/s10637-014-0120-7
PMID: 24919854
قاعدة البيانات: MEDLINE
الوصف
تدمد:1573-0646
DOI:10.1007/s10637-014-0120-7