CT52923
目录号 : GC67774CT52923 是一种选择性的血小板衍生生长因子受体 (PDGFR) 拮抗剂，具有口服活性。CT52923 也是一种 ATP 竞争性抑制剂。CT52923 可用于病理疾病的研究，包括动脉粥样硬化、肾小球肾炎、肝硬化、肺纤维化和癌症。
Cas No.:205256-55-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
CT52923 is a selective, orally active platelet-derived growth factor receptor (PDGFR) antagonist. CT52923 also is an ATP-competitive inhibitor. CT52923 can be used for the research variety of pathological diseases, including atherosclerosis, glomerulonephritis, liver cirrhosis, pulmonary fibrosis, and cancer[1].
CT52923 抑制 PDGFRs 和干细胞因子受体，IC50 值为 100 至 200 nM[1]。
CT52923（0.01-30 μM；24 h）阻断血小板衍生生长因子诱导的平滑肌细胞迁移或成纤维细胞增殖，IC50 分别为 64 和 280 nM[1]。
Cell Migration Assay [1]
| Cell Line: | Rat A10 smooth muscle cells |
| Concentration: | 0.01-30 μM |
| Incubation Time: | 24 h |
| Result: | Inhibited PDGF-induced cell migration with an IC50 of 64 nM. |
CT52923（口服；5、15、30 和 50 mg/kg；每日两次）可显著抑制大鼠颈动脉损伤后内膜新生的形成[1]。
| Animal Model: | Rat carotid artery balloon angioplasty model[1]. |
| Dosage: | 5, 15, 30, and 50 mg/kg |
| Administration: | Oral gavage; twice daily |
| Result: | Inhibited PDGF-mediated response to vascular injury. |
[1]. J C Yu, et al. Efficacy of the novel selective platelet-derived growth factor receptor antagonist CT52923 on cellular proliferation, migration, and suppression of neointima following vascular injury. J Pharmacol Exp Ther. 2001 Sep;298(3):1172-8.
| Cas No. | 205256-55-9 | SDF | Download SDF |
| 分子式 | C23H25N5O4S | 分子量 | 467.54 |
| 溶解度 | 储存条件 | 4°C, protect from light | |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1389 mL | 10.6943 mL | 21.3885 mL |
| 5 mM | 0.4278 mL | 2.1389 mL | 4.2777 mL |
| 10 mM | 0.2139 mL | 1.0694 mL | 2.1389 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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2.
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Efficacy of the novel selective platelet-derived growth factor receptor antagonist CT52923 on cellular proliferation, migration, and suppression of neointima following vascular injury
J Pharmacol Exp Ther 2001 Sep;298(3):1172-8.PMID:11504817doi
Exaggerated or inappropriate signaling by the platelet-derived growth factor receptor (PDGFR) tyrosine kinase has been implicated in a wide variety of diseases. Thus, a series of piperazinyl quinazoline compounds were identified as potent antagonists of the PDGFR by screening chemical libraries. An optimized analog, CT52923, was shown to be an ATP-competitive inhibitor that exhibited remarkable specificity when tested against other kinases, including all members of the closely related PDGFR family. The PDGFRs and stem cell factor receptor were inhibited with an IC(50) of 100 to 200 nM, while 45- to >200-fold higher concentrations of CT52923 were required to inhibit fms-like tyrosine kinase-3 and colony-stimulating factor-1 receptor, respectively. Other receptor tyrosine kinases, cytoplasmic tyrosine kinases, serine/threonine kinases, or members of the mitogen-activated protein kinase pathway were not significantly inhibited at 100- to 1000-fold higher concentrations. In addition, this compound also demonstrated specificity for inhibition of cellular responses. Platelet-derived growth factor-induced smooth muscle cell migration or fibroblast proliferation was found to be blocked by CT52923 with an IC(50) of 64 and 280 nM, respectively, whereas 50- to 100-fold higher concentrations were required to inhibit these responses when induced with fibroblast growth factor. To investigate the effect of CT52923 on PDGFR signaling, in vivo studies demonstrated that CT52923 could significantly inhibit neointima formation following carotid artery injury by oral administration in the rat. Therefore, PDGFR antagonism by CT52923 could be a viable strategy for the prevention of clinical restenosis or the treatment of other human diseases involving PDGFR signaling.
Platelet-derived growth factor (PDGF) autocrine signaling regulates survival and mitogenic pathways in glioblastoma cells: evidence that the novel PDGF-C and PDGF-D ligands may play a role in the development of brain tumors
Cancer Res 2002 Jul 1;62(13):3729-35.PMID:12097282doi
Glioblastoma multiforme, the most common form of malignant brain tumor,is resistant to all forms of therapy and causes death within 9-12 months of diagnosis. Glioblastomas are known to contain numerous genetic and physiological alterations affecting cell survival and proliferation; one of the most common alterations being platelet-derived growth factor (PDGF) autocrine signaling characterized by coexpression of PDGF and its receptor. The PDGF family consists of four members, PDGF-A, -B, -C, and -D, that signal through the alpha and beta PDGF receptor (PDGFR) tyrosine kinases. Numerous studies have demonstrated expression of PDGF-A, PDGF-B, and the PDGFRs in gliomablastomas, but such studies have not been conducted for the newly identified PDGF-C and -D. Therefore, we examined the expression of all PDGF ligands and receptors in 11 glioma cell lines and 5 primary glioblastoma tumor tissues by quantitative reverse transcription-PCR. Expression of PDGF/PDGFR pairs that are known to functionally interact were identified in all of the samples. Interestingly, PDGF-C expression was ubiquitous in brain tumor cells and tissues but was very low or absent in normal adult and fetal brain. PDGF-D was expressed in 10 of 11 brain tumor cell lines and 3 of 5 primary brain tumor samples. As a strategy for blocking PDGFR signaling, CT52923, a potent selective small molecule piperazinyl quinazoline kinase inhibitor of the PDGFR, was identified. In model systems using NIH/3T3 cells, CT52923 blocked PDGF autocrine-mediated phosphorylation of PDGFR, Akt, and mitogen-activated protein kinase (MAPK), while having no effect on v-fms or V12-ras-mediated Akt or extracellular signal-regulated protein kinase (Erk) phosphorylation. More importantly, p.o. administration of CT52923 to nude mice caused a significant 61% reduction (P < 0.006) in tumor growth of NIH/3T3 cells transformed by PDGF, whereas tumor formation by cells expressing v-fms was unaffected. We next characterized PDGF autocrine signaling in five glioblastoma cell lines. In all of the cases, PDGF autocrine signaling was evident because treatment with 1-10 microM CT52923 inhibited PDGFR autophosphorylation when present at a detectable level and blocked downstream Akt and/or Erk phosphorylation. The functional significance of PDGF autocrine signaling in these cells was demonstrated by the fact that the CT52923 inhibited soft agar colony formation, and, when given p.o. to nude mice, it effectively reduced tumor formation by 44% (P < 0.0019) after s.c. injection of C6 glioblastoma cells. This study of glioblastoma cells and primary tissues is the first to implicate PDGF-C and -D in brain tumor formation and confirms the existence of autocrine signaling by PDGF-A and -B. More importantly, treatment with the PDGFR antagonist CT52923 inhibited survival and/or mitogenic pathways in all of the glioblastoma cell lines tested and prevented glioma formation in a nude mouse xenograft model. Together these findings demonstrate the potential therapeutic utility of this class of compounds for the treatment of glioblastoma.
Autocrine platelet-derived growth factor-dependent gene expression in glioblastoma cells is mediated largely by activation of the transcription factor sterol regulatory element binding protein and is associated with altered genotype and patient survival in human brain tumors
Cancer Res 2005 Jul 1;65(13):5523-34.PMID:15994924DOI:10.1158/0008-5472.CAN-04-2582.
A complex profile of gene expression elicited by autocrine platelet-derived growth factor (PDGF) signaling was identified in U87 MG glioblastoma cells by microarray analysis. The most striking pattern observed was a PDGF-dependent activation of at least 25 genes involved with biosynthesis and/or uptake of cholesterol and isoprenoids, including mevalonate pyrophosphate decarboxylase, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase, HMG-CoA reductase, and low-density lipoprotein receptor. Activity of the HMG-CoA synthase promoter was induced by autocrine PDGF activity as indicated by significant reductions following forced expression of dominant-negative PDGF-A (88%) or treatment with the PDGF receptor antagonist CT52923 (50%). Induction of the HMG-CoA synthase promoter required a binding site for sterol regulatory element binding proteins (SRE-BP), consistent with a key role for these transcription factors in the induction of this gene network. Neither proteolytic activation nor nuclear localization of SRE-BP was affected by disruption of the PDGF autocrine loop, indicating that PDGF signaling is required for other signaling events involved in activation of SRE-BP target genes. Analysis of an expression databank derived from human glial tumors (n = 77) identified a subgroup exhibiting a profile consistent with PDGF dependence, including increased expression of SRE-BP target genes. This subgroup displayed an absence of epidermal growth factor receptor gene amplification, decreased incidence of allelic loss of 10q, increased frequency of TP53 mutations and allelic losses of 1p and 19q, and longer patient survival. This study identifies genes associated with oncogenic activity of PDGF and provides important insights into biomarkers and therapeutic targets in malignant gliomas.
Potent and selective inhibitors of PDGF receptor phosphorylation. 2. Synthesis, structure activity relationship, improvement of aqueous solubility, and biological effects of 4-[4-(N-substituted (thio)carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline derivatives
J Med Chem 2002 Sep 26;45(20):4513-23.PMID:12238930DOI:10.1021/jm0201114.
4-[4-(N-Substituted (thio)carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline derivatives such as KN1022 are potent inhibitors of the phosphorylation of platelet derived growth factor receptor (PDGFR). Structure activity relationships in the (thio)urea moiety, the phenyl ring itself, the linker between these two moieties, and the piperazine moiety were investigated. The role of the linker was found to be quite different, where ureas yielded decreasing activity, while thioureas provided increasing activity. Cyanoguanidine as a bioisostere of thiourea and related dicyanovinyl or nitrovinyl groups were not suitable for potent activity. A hydrogen atom on the (thio)urea moiety was essential for activity. Stereochemistry was also important for inhibition of PDGFR phosphorylation. Through the modification of these moieties, benzylthiourea analogues with a small substituent on the 4-position and the 3,4-methylenedioxy group (KN734/CT52923) were found to be optimal for selective and potent activity. Replacement of the phenyl ring by heterocycles improved aqueous solubility without loss of activity and kinase selectivity. Introduction of a methyl group on 5-position of the piperazine ring and replacement by homopiperazine reduced inhibitory activity. An efficient synthetic method was also developed for 2-pyridylurea-containing analogues, via carbonylation of 2-aminopyridine with N,N'-carbonyldiimidazole. A potent analogue, KN734, inhibited smooth muscle cell proliferation and migration induced by platelet derived growth factor-BB (PDGF-BB) and suppressed neointima formation following balloon injury in rat carotid artery by oral administration. Therefore, 4-[4-(N-substituted (thio)carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline derivatives may be expected to have potential as therapeutic agents for the treatment of restenosis.