生物活性

• 靶点	TGFβR1 IC50:56nM

• 描述The TGF-β pathway regulates a wide variety of cellular processes in many different cell types and biological contexts. There are three identified TGF receptor ligands, TGF-β1, 2, and 3. Activated TGF-β ligands can interact with TGF-β type II receptors (TβRII), then recruit and phosphorylate the TGF-β type I receptors (also called as TβRI or ALK5). In turn, activated TβRI phosphorylates SMAD2 and SMAD3 at C-terminal serine residues. Following that, phosphorylated SMAD and SMAD3 assemble into heterodimeric and trimeric complexes with SMAD4. Then the trimeric complex translocate into the nucleus and regulate the expression of TGF-β target genes^[1]. LY2157299 (Galunisertib) is a selective TGF-β1 Type I receptor inhibitor with IC50 values of 0.17, 0.21 and 0.08 nM for TGF-βRI, TGF-βRII and ALK4 (measure by kinase assays)^[2] Pre-treatment with 0.5 μM LY2157299 for 1h can abolish or reduce SMAD2 phosphorylation induced by TGF-β-activated TBRI in HS-5 and K562 cells. After 14 days of oral administration of LY-2157299, 100 mg/kg, daily, anemia in a model of bone marrow failure was improved. LY-2157299 can result in a significant increase in erythroid and myeloid colony numbers in all patients, which pointed to a high therapeutic potential of TβRI inhibition by LY2157299 in low-grade MDS^[3]. Orally administered with LY2157299 (75 mg/kg, bid) significantly suppress growth of transplanted tumors in B16 cells xenograft mice^[4]. Up to now, a phase 3 study of LY2157299 treatment for Myelodysplastic Syndromes, as well as phase 2 studies of LY2157299 treatment for glioma has been completed. The phase 2 studies of LY2157299 treatment for solid tumor, non-small cell lung cancer recurrent and hepatocellular carcinoma recurrent are recruiting (see https://www.clinicaltrials.gov/).
• 作用机制LY2157299 binds to the ATP-binding site of TGFβRI.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  Panc-1	10 μM	Function Assay	48 h	stimulates the cell invasion into the collagen gel and the Matrigel-coated collagen gel	24780821

• 动物研究
  剂量	Mice[6] (p.o.): 150 mg/kg, 1.5 mg/kg (i.v.)
  给药途径	p.o., i.v.
  动物药代数据	Animal Nude mice[7] Dose 75 mg/kg Administration p.o. VT/F 2.02 ± 0.11 L V/F 0.64 ± 0.58 L CLD/F 1.05 ± 0.33 L/h Cl/F 0.57 ± 0.08 L/h

• 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
  NCT03206177	Carcinosarcoma, Ovarian	Phase 1	Recruiting	June 1, 2022	United States, Oklahoma ... more >> University of Oklahoma Health Sciences Center Recruiting Oklahoma City, Oklahoma, United States, 73104 Contact: Kathleen Moore, MD Collapse <<
  NCT01373164	Neoplasms Neo... more >>plasm Metastasis Pancreatic Cancer Collapse <<	Phase 1 Phase 2	Completed	-	United States, Florida ... more >> Florida Hospital Tampa HPG and Foregut Surgery Tampa, Florida, United States, 33613 United States, Illinois Ingalls Memorial Hospital Harvey, Illinois, United States, 60426 United States, Washington Seattle Cancer Care Alliance Seattle, Washington, United States, 98109 Belgium 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. Brussel, Belgium, 1000 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. Liège, Belgium, 4000 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. Besancon, France, 25030 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. Clermont-Ferrand, France, 63003 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, 13273 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. Montbéliard, France, 25250 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. Paris, France, 75674 Germany 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. Frankfurt, Germany, 60596 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. Friedrichshafen, Germany, 88045 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. Leipzig, Germany, 04103 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. Marburg, Germany, 35043 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. Munich, Germany, 81925 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. Mönchengladbach, Germany, 41063 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. Reutlingen, Germany, 72764 Italy 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. Bergamo, Italy, 24128 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. Bologna, Italy, 40138 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. Verona, Italy, 37134 Spain 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. Barcelona, Spain, 08035 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. Madrid, Spain, 28033 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. Pozuelo De Alarcon, Spain, 28223 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. Sevilla, Spain, 41013 Collapse <<
  NCT01373164	-	-	Completed	-	-

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• 参考文献

• [1] Colak S, Ten Dijke P, et al. Targeting TGF-β Signaling in Cancer. Trends Cancer. 2017 Jan;3(1):56-71.

  [2] Herbertz S, Sawyer JS, et al. Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway. Drug Des Devel Ther. 2015 Aug 10;9:4479-99.

  [3] Zhou L, McMahon C, et al. Reduced SMAD7 leads to overactivation of TGF-beta signaling in MDS that can be reversed by a specific inhibitor of TGF-beta receptor I kinase. Cancer Res. 2011 Feb 1;71(3):955-63.

  [4] Yoon JH, Jung SM, et al. Activin receptor-like kinase5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby derepressing eomesodermin in cytotoxic T lymphocytes. EMBO Mol Med. 2013 Nov;5(11):1720-39.

  [5] Yingling JM, McMillen WT, et al. Preclinical assessment of galunisertib (LY2157299 monohydrate), a first-in-class transforming growth factor-β receptor type I inhibitor. Oncotarget. 2017 Dec 31;9(6):6659-6677.

  [6] Faivre S, Santoro A, et al. Novel transforming growth factor beta receptor I kinase inhibitor galunisertib (LY2157299) in advanced hepatocellular carcinoma. Liver Int. 2019 Aug;39(8):1468-1477.

  [7] Bueno L, de Alwis DP, et al. Semi-mechanistic modelling of the tumour growth inhibitory effects of LY2157299, a new type I receptor TGF-beta kinase antagonist, in mice. Eur J Cancer. 2008 Jan;44(1):142-50. Epub 2007 Nov 26.

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