生物活性

• 靶点

  Abl (virus) IC50:0.6μM

  c-Kit IC50:0.1μM

  PDGFR IC50:0.1μM

• 描述Imatinib Mesylate is the mesylate form of Imatinib. Imatinib is a multiple target inhibitor with IC50 values of 100nM, 100nM, 38nM, 25nM and 25nM for PDGFR, c-kit, v-Abl, c-abl and bcr-abl (measured by in vitro enzyme assays), respectively, usually used for treatment of chronic myelogenous leukemia (CML)^[1][2][3]. In cellular study showed that treatment with Imatinib for 90min could selectively inhibited the autophosphorylation of v-AbI at concentration>3μM in PB-3c cI. 15 cells, PDGF-BB-induced autophosphorylation of PDGFR at concentration>0.3μM in BALB/c 313 cells^[1], steel factor–dependent phosphorylation of c-kit and steel factor-dependent activation of Akt at concentration>1μM in M-07e cells, as well as autophosphorylation of an activated mutant form of c-kit and c-kit–dependent activation of MAP kinase/AKT at concentration>0.1μM in HMC-1 cells. Consistent with this, Imatinib showed anti- proliferative effect on HMC-1 cells by 90%-95% at concentration ranging in 0.1μM-10μM, which may due to the abrogation by Imatinib of antiapoptotic effect of mutant c-kit activation. ^[2]. Intraperitoneal injection with Imatinib at dose of 50mg/kg once daily for 30 days suppressed tumor growth in BALB/c AMuLV and BALB/c 3T3 v-sis cells xenograft mice^[1].
• 作用机制Imatinib can bind with the ATP binding site of BCR/ABL tyrosine kinase, thus keeps BCR/ABL in an inactive form^[4].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  DU145	20 μM	Cell Viability Assay	6-72 h	decreases cell viability	25786656
  DU145	20 μM	Apoptosis Assay	48/72 h	induces cell death by apoptosis	25786656
  GIST882	-	Growth Inhibition Assay	96 h	IC50=1.7 μM	24900212

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• 动物研究
  剂量	Mice: 50 mg/kg, 150 mg/kg[5] (i.p.); 100 mg/kg, 200 mg/kg[6] (p.o.)
  给药途径	i.p., p.o.

• 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
  NCT00477269	Pulmonary Arterial Hypertensio... more >>n Collapse <<	Phase 2 Phase 3	Completed	-	United States, California ... more >> Novartis Investigative Site Los Angeles, California, United States, 90073 United States, New Jersey Novartis investigative site Newark, New Jersey, United States, 07112 United States, New York Novartis Investigative Site New York, New York, United States, 10032 Austria Novartis Investigative Site Graz, Austria, A-8036 Novartis Investigative site Graz, Austria Germany Novartis Investigative Site Giessen, Germany, 35385 Novartis Investigative site Giessen, Germany Novartis Investigative Site Hannover, Germany, 30625 Novartis Investigative site Hannover, Germany United Kingdom Novartis Investigative Site Cambridge, Cambridgeshire, United Kingdom, CB23 3RE Novartis Investigative Site Glasgow, United Kingdom, G11 6NT Novartis Investigative site Glasgow, United Kingdom Novartis Investigative site Papworth, United Kingdom Collapse <<
  NCT01991379	Gastrointestinal Stromal Tumor... more >> (GIST) Collapse <<	Phase 1 Phase 2	Recruiting	November 2021	United States, New York ... more >> Memorial Sloan Kettering Cancer Center Recruiting New York, New York, United States, 10065 Contact: Ping Chi, MD    646-888-4166       Contact: William Tap, MD    646-888-4163       Principal Investigator: Ping Chi, MD, PhD Collapse <<
  NCT00026169	Malignant Neoplasm ... more >> Unspecified Adult Solid Tumor, Protocol Specific Collapse <<	Phase 1	Completed	-	United States, Ohio ... more >> Case Western Reserve University Cleveland, Ohio, United States, 44106 Collapse <<

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• 参考文献

• [1] Buchdunger E, Zimmermann J, et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res. 1996 Jan 1;56(1):100-4.

  [2] Heinrich MC, Griffith DJ, et al. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood. 2000 Aug 1;96(3):925-32.

  [3] Druker BJ, Tamura S, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996 May;2(5):561-6.

  [4] Marcucci G, Perrotti D, et al. Understanding the molecular basis of imatinib mesylate therapy in chronic myelogenous leukemia and the related mechanisms of resistance. Commentary re: A. N. Mohamed et al., The effect of imatinib mesylate on patients with Philadelphia chromosome-positive chronic myeloid leukemia with secondary chromosomal aberrations. Clin. Cancer Res., 9: 1333-1337, 2003. Clin Cancer Res. 2003 Apr;9(4):1248-52.