دورية أكاديمية
A novel CDK9 inhibitor shows potent antitumor efficacy in preclinical hematologic tumor models.
العنوان: | A novel CDK9 inhibitor shows potent antitumor efficacy in preclinical hematologic tumor models. |
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المؤلفون: | Yin T; Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom., Lallena MJ; Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom., Kreklau EL; Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom., Fales KR; Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom., Carballares S; Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom., Torrres R; Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom., Wishart GN; Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom., Ajamie RT; Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom., Cronier DM; Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom., Iversen PW; Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom., Meier TI; Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom., Foreman RT; Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom., Zeckner D; Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom., Sissons SE; Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom., Halstead BW; Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom., Lin AB; Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom., Donoho GP; Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom., Qian Y; Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom., Li S; Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom., Wu S; Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom., Aggarwal A; Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom., Ye XS; Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom., Starling JJ; Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom., Gaynor RB; Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom., de Dios A; Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom du_jian@lilly.com de_dios_alfonso@lilly.com., Du J; Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom du_jian@lilly.com de_dios_alfonso@lilly.com. |
المصدر: | Molecular cancer therapeutics [Mol Cancer Ther] 2014 Jun; Vol. 13 (6), pp. 1442-56. Date of Electronic Publication: 2014 Mar 31. |
نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: American Association for Cancer Research, Inc Country of Publication: United States NLM ID: 101132535 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-8514 (Electronic) Linking ISSN: 15357163 NLM ISO Abbreviation: Mol Cancer Ther Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: Philadelphia, PA : American Association for Cancer Research, Inc., c2001- |
مواضيع طبية MeSH: | Antineoplastic Agents/*administration & dosage , Apoptosis/*drug effects , Cyclin-Dependent Kinase 9/*genetics , Cyclohexylamines/*administration & dosage , Indazoles/*administration & dosage , Leukemia/*drug therapy, Cell Line, Tumor ; Cyclin-Dependent Kinase 9/antagonists & inhibitors ; Humans ; Leukemia/pathology ; Myeloid Cell Leukemia Sequence 1 Protein/biosynthesis ; Phosphorylation/drug effects ; Serine/metabolism |
مستخلص: | DNA-dependent RNA polymerase II (RNAP II) largest subunit RPB1 C-terminal domain (CTD) kinases, including CDK9, are serine/threonine kinases known to regulate transcriptional initiation and elongation by phosphorylating Ser 2, 5, and 7 residues on CTD. Given the reported dysregulation of these kinases in some cancers, we asked whether inhibiting CDK9 may induce stress response and preferentially kill tumor cells. Herein, we describe a potent CDK9 inhibitor, LY2857785, that significantly reduces RNAP II CTD phosphorylation and dramatically decreases MCL1 protein levels to result in apoptosis in a variety of leukemia and solid tumor cell lines. This molecule inhibits the growth of a broad panel of cancer cell lines, and is particularly efficacious in leukemia cells, including orthotopic leukemia preclinical models as well as in ex vivo acute myeloid leukemia and chronic lymphocytic leukemia patient tumor samples. Thus, inhibition of CDK9 may represent an interesting approach as a cancer therapeutic target, especially in hematologic malignancies. (©2014 American Association for Cancer Research.) |
المشرفين على المادة: | 0 (Antineoplastic Agents) 0 (Cyclohexylamines) 0 (Indazoles) 0 (MCL1 protein, human) 0 (Myeloid Cell Leukemia Sequence 1 Protein) 0 (N1-(4-(3-isopropyl-2-methylindazol-5-yl)pyrimidin-2-yl)-N4-tetrahydropyran-4-yl-cyclohexane-1,4-diamine) 452VLY9402 (Serine) EC 2.7.11.22 (CDK9 protein, human) EC 2.7.11.22 (Cyclin-Dependent Kinase 9) |
تواريخ الأحداث: | Date Created: 20140402 Date Completed: 20150219 Latest Revision: 20200930 |
رمز التحديث: | 20221213 |
DOI: | 10.1158/1535-7163.MCT-13-0849 |
PMID: | 24688048 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1538-8514 |
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DOI: | 10.1158/1535-7163.MCT-13-0849 |