GGTI-2154
目录号 : GC62633GGTI-2154 是一种有效和选择性的 geranylgeranyltransferase I (GGTase I) 抑制剂,IC50 值为 21 nM。GGTI-2154 对 GGTase I 的选择性是 FTase (IC50=5600 nM) 的 200 倍以上。GGTI-2154 可用于癌症的研究。
Cas No.:251577-10-3
Sample solution is provided at 25 µL, 10mM.
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GGTI-2154 is a potent and selective inhibitor of geranylgeranyltransferase I (GGTase I), with an IC50 of 21 nM. GGTI-2154 shows more than 200-fold selectivity for GGTase I over FTase (IC50=5600 nM). GGTI-2154 can be used for the research of cancer[1][2].
GGTI-2154 inhibits the transfer of geranylgeranyl from [3H]GGPP to H-Ras CVLL, with an IC50 of 21 nM[1].
GGTI-2154 (100 mg/kg/day; s.c. for 14 days) induces breast tumor regression in MMTV-Ν-Ha-Ras transgenic mice[2].GGTI-2154 (50 mg/kg/day; i.p. for 50 day) inhibits A-549 tumor growth in nude mice by 60%[1].
[1]. Sun J, et, al. Antitumor efficacy of a novel class of non-thiol-containing peptidomimetic inhibitors of farnesyltransferase and geranylgeranyltransferase I: combination therapy with the cytotoxic agents cisplatin, Taxol, and gemcitabine. Cancer Res. 1999 Oct 1;59(19):4919-26.
[2]. Sun J, et, al. Geranylgeranyltransferase I inhibitor GGTI-2154 induces breast carcinoma apoptosis and tumor regression in H-Ras transgenic mice. Cancer Res. 2003 Dec 15;63(24):8922-9.
Cas No. | 251577-10-3 | SDF | |
分子式 | C24H28N4O3 | 分子量 | 420.5 |
溶解度 | 储存条件 | Store at -20°C | |
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10 mM | 0.2378 mL | 1.1891 mL | 2.3781 mL |
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Geranylgeranyltransferase I inhibitor GGTI-2154 induces breast carcinoma apoptosis and tumor regression in H-Ras transgenic mice
Cancer Res 2003 Dec 15;63(24):8922-9.PMID:14695209doi
Treatment of H-Ras transgenic mice with the geranylgeranyltransferase I (GGTase I) inhibitor GGTI-2154 results not only in halting the growth of aggressive breast tumors but actually in inducing the regression (54 +/- 3%) of all 19 tumors analyzed. The farnesyltransferase (FTase) inhibitor FTI-2148 induced an average of 87 +/- 3% regression in the 13 tumors analyzed. GGTase I, but not FTase, is inhibited in breast tumors after treatment with GGTI-2154, whereas in tumors from mice treated with FTI-2148, only FTase is inhibited. The processing of the geranylgeranylated proteins RhoA, Rap1, and R-Ras, but not the farnesylated proteins H-Ras and HDJ-2, is inhibited in tumors obtained from mice treated with GGTI-2154. GGTI-2154 and FTI-2148 suppress constitutively activated phospho-Erk1/2 and phospho-Akt, induce apoptosis, and induce differentiation toward ductolobular breast epithelium. The data demonstrate that geranylgeranylated proteins are critical in H-Ras oncogenesis in vivo and give strong support for GGTase I as a target for anticancer drug discovery.
Antitumor efficacy of a novel class of non-thiol-containing peptidomimetic inhibitors of farnesyltransferase and geranylgeranyltransferase I: combination therapy with the cytotoxic agents cisplatin, Taxol, and gemcitabine
Cancer Res 1999 Oct 1;59(19):4919-26.PMID:10519405doi
Ras malignant transformation requires posttranslational modification by farnesyltransferase (FTase). Here we report on the design and antitumor activity, in monotherapy as well as in combination therapy with cytotoxic agents, of a novel class of non-thiol-containing peptidomimetic inhibitors of FTase and the closely related family member geranylgeranyltransferase I (GGTase I). The non-thiol-containing FTI-2148 is highly selective for FTase (IC50, 1.4 nM) over GGTase I (IC50, 1700 nM), whereas GGTI-2154 is highly selective for GGTase I (21 nM) over FTase (IC50, 5600 nM). In whole cells, the corresponding methylester prodrug FTI-2153 is >3000-fold more potent at inhibiting H-Ras (IC50, 10 nM) than Rap1A processing, whereas GGTI-2166 is over 100-fold more selective at inhibiting Rap1A (IC50, 300 nM) over H-Ras processing. Furthermore, FTI-2153 was highly effective at suppressing oncogenic H-Ras constitutive activation of mitogen-activated protein kinase and human tumor growth in soft agar. FTI-2148 suppressed the growth of the human lung adenocarcinoma A-549 cells in nude mice by 33, 67, and 91% in a dose-dependent manner. Combination therapy of FTI-2148 with either cisplatin, gemcitabine, or Taxol resulted in a greater antitumor efficacy than monotherapy. GGTI-2154 in similar antitumor efficacy experiments is less potent than FTI-2148 and inhibits tumor growth by 9, 27, and 46%. Combination therapy of GGTI-2154 with cisplatin, gemcitabine, or Taxol is also more effective. Finally, FTI-2148 and GGTI-2154 are 30- and 33-fold more selective and 30- and 16-fold more potent in whole cells than our previously reported thiol-containing FTI-276 and GGTI-297, respectively. Thus, our results demonstrate that this highly potent and selective novel class of non-thiol-containing peptidomimetics inhibits human tumor growth in whole animals and that combination therapy with cytotoxic agents is more beneficial than monotherapy.