生物活性

• 描述Receptor tyrosine kinases (RTK) are mediators of cellular proliferation. These transmembrane RTKs contain an extracellular domain for ligand binding and intracellular kinase domains that mediate autophosphorylation, recruitment of downstream signaling molecules, and signal transduction. Type III RTKs, such as PDGFR (platelet-derived growth factor receptor), FGFR (fibroblast growth factor receptor), VEGFR (vascular endothelial growth factor receptor), FLT3 and c-KIT are often overexpressed in tumor and implicated in tumor growth and progression^[3]. Tandutinib is an inhibitor of FLT3, PDGFR and c-Kit. The kinase inhibitory IC₅₀s were 0.22, 0.20 and 0.17 μM, respectively. Tandutinib inhibited phosphorylation of WT FLT3 and FLT3-ITD (internal tandem duplication) in Ba/F3 cells with IC₅₀s of 30-100nM. Tandutinib inhibited cell proliferation of the FLT3-ITD-positive cells (Molm-13 and Molm-14 cells） with an IC₅₀ value of 10 nM, whereas the FLT3-ITD-negative cells (THP-1, KG-1, and RS4 cells) were resistant, requiring 1000-fold higher concentrations to inhibit cell growth. Treatment of Molm-14 cells with 1 μM tandutinib resulted in an increase of the percentage of apoptotic cells from a background level of 5% to 51% at 24h and 78% at 96h^[6]. Tandutinib preferentially inhibited the growth of blast colonies derived from FLT3 ITD-positive patients with IC₅₀s between 75 and 400 nM^[7]. In a nude mice model established by injection of FLT3-ITD-transformed Ba/F3 cells, oral administration of tandutinib at 60 mg/kg bid significantly increased the survival of mice and resulted in a significant reduction in mortality in a mouse bone marrow transplantation model^[6].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  5637	1-10 μM	Cell Viability Assay	72 h	inhibits cell growth in a dose dependent manner	24325461
  8226	-	Growth Inhibition Assay	72 h	IC50> 2500 nM	15598814
  97-7	-	Growth Inhibition Assay	5 d	IC50=1000 nM	21119661

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• 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
  NCT02558387	Recurrent or Metastatic Saliva... more >>ry Gland Cancer of the Head and Neck Collapse <<	Phase 2	Unknown	January 2017	Korea, Republic of ... more >> Samsung Medical Center Seoul, Korea, Republic of, 135-710 Collapse <<
  NCT01155713	Neoplasm Canc... more >>er Tumors Collapse <<	Phase 1	Completed	-	United States, Arizona ... more >> Scottsdale Healthcare/TGen Clinical Research Service TGen Clinical Research Service Scottsdale, Arizona, United States, 85258 United States, North Carolina Duke University Medical Center Durham, North Carolina, United States, 27710 United States, Tennessee Sarah Cannon Research Institute Sarah Cannon Research Instit Nashville, Tennessee, United States, 37203 United States, Utah University of Utah / Huntsman Cancer Institute Salt Lake City, Utah, United States, 84112 Collapse <<
  NCT01421004	Advanced Solid Tumors ... more >> Excluding Breast Cancer Collapse <<	Phase 1	Completed	-	United States, California ... more >> City of Hope National Medical Center SC-2 Duarte, California, United States, 91010-3000 University of California at Los Angeles UCLA LeConte Location Los Angeles, California, United States, 90095 University of California San Francisco UCSF (SC) San Francisco, California, United States, 94101 United States, Florida Florida Cancer Specialists Sarasota Office Fort Myers, Florida, United States, 33901 United States, Illinois Rush University Medical Center Rush 3 Chicago, Illinois, United States, 60612 United States, Missouri Washington University School of Medicine SC St. Louis, Missouri, United States, 63110 United States, New York Montefiore Medical Center Montefiore Medical Center (SC) Bronx, New York, United States, 10467 United States, Oklahoma University of Oklahoma Health Sciences Center OUHSC - SC Oklahoma City, Oklahoma, United States, 73104 United States, Pennsylvania University of Pittsburgh Cancer Institute Pittsburgh, Pennsylvania, United States, 15232-1305 United States, Tennessee Sarah Cannon Research Institute Sarah Cannon Research (SC) Nashville, Tennessee, United States, 37203 United States, Texas Sammons Cancer Center - Texas Oncology SC-2 Dallas, Texas, United States, 78246 Cancer Therapy & Research Center / UT Health Science Center InstituteForDrugDevelopment(5) San Antonio, Texas, United States, 78229 United States, Utah University of Utah / Huntsman Cancer Institute Huntsman Salt Lake City, Utah, United States, 84112 United States, Wisconsin University of Wisconsin Univ Wisc Madison, Wisconsin, United States, 53792 Collapse <<

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• 参考文献

• [1] Huynh H, Chow PK, et al. Dovitinib demonstrates antitumor and antimetastatic activities in xenograft models of hepatocellular carcinoma. J Hepatol. 2012 Mar;56(3):595-601.

  [2] Huynh H, Chow PK, et al. Dovitinib demonstrates antitumor and antimetastatic activities in xenograft models of hepatocellular carcinoma. J Hepatol. 2012 Mar;56(3):595-601.

  [3] Lee SH, Lopes de Menezes D, Vora J, Harris A, Ye H, Nordahl L, Garrett E, Samara E, Aukerman SL, Gelb AB, Heise C. In vivo target modulation and biological activity of CHIR-258, a multitargeted growth factor receptor kinase inhibitor, in colon cancer models. Clin Cancer Res. 2005 May 15;11(10):3633-41. doi: 10.1158/1078-0432.CCR-04-2129. PMID: 15897558.

  [4] Trudel S, Li ZH, Wei E, Wiesmann M, Chang H, Chen C, Reece D, Heise C, Stewart AK. CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood. 2005 Apr 1;105(7):2941-8.

  [5] Eucker J, Zang C, Zhou Y, Li X, Habbel P, Schulz CO, Scholz C, Liu H. TKI258, a multi-tyrosine kinase inhibitor is efficacious against human infant/childhood lymphoblastic leukemia in vitro. Anticancer Res. 2014 Sep;34(9):4899-907.

  [6] Kelly LM, Yu JC, Boulton CL, Apatira M, Li J, Sullivan CM, Williams I, Amaral SM, Curley DP, Duclos N, Neuberg D, Scarborough RM, Pandey A, Hollenbach S, Abe K, Lokker NA, Gilliland DG, Giese NA. CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML). Cancer Cell. 2002 Jun;1(5):421-32. doi: 10.1016/s1535-6108(02)00070-3. PMID: 12124172.

  [7] Griswold IJ, Shen LJ, La Rosée P, Demehri S, Heinrich MC, Braziel RM, McGreevey L, Haley AD, Giese N, Druker BJ, Deininger MW. Effects of MLN518, a dual FLT3 and KIT inhibitor, on normal and malignant hematopoiesis. Blood. 2004 Nov 1;104(9):2912-8. doi: 10.1182/blood-2003-05-1669. Epub 2004 Jul 8. PMID: 15242881.

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