GGTI 298 | 180977-44-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: GGTI 298
• 英文别名: (S)-methyl 2-(4-(((R)-2-amino-3-mercaptopropyl)amino)-2-(naphthalen-1-yl)benzamido)-4-methylpentanoate；methyl (2S)-2-[[4-[[(2R)-2-amino-3-sulfanylpropyl]amino]-2-naphthalen-1-ylbenzoyl]amino]-4-methylpentanoate
• CAS: 180977-44-0
• 化学式: C₂₇H₃₃N₃O₃S
• 分子量: 479.643
• InChiKey: XVWPFYDMUFBHBF-CLOONOSVSA-N

物化性质

• 熔点：
  99.5-100 °C
• 沸点：
  673.7±55.0 °C(Predicted)
• 密度：
  1.190±0.06 g/cm3(Predicted)
• 溶解度：
  二甲基亚砜：22 mg/毫升

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  34
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  94.4
• 氢给体数：
  4
• 氢受体数：
  6

制备方法与用途

生物活性

GGTI298 是有效的 GGTase I 抑制剂，能够抑制 geranylgeranylated Rap1A 的过程，并对 farnesylated Ha-Ras 也有一定影响。在体内实验中，其对 Rap1A 和 Ha-Ras 的 IC50 值分别为 3 μM 和 >20 μM。

靶点

• IC50:
  • Rap1A (in vivo): 3 μM
  • Ha-Ras (in vivo): >20 μM

体外研究

GGTI298 作为 RhoA 抑制剂，在刺激 cAMP 后显著减少了 IK(ap) 的活性。同时，H1152（ROCK 抑制剂）还减少了 KCNN4c 与顶端膜标记物 WGA 在 T84WT 细胞中的共定位。

敲除 DR4 可以阻断 NF-κB 活化，并使 GGTI298 和 TRAIL 联合诱导的 DR5 依赖性凋亡更加敏感。GGTI298/TRAIL 通过激活 NF-κB 并抑制 Akt 来发挥作用。

敲除 DR5 阻止了 GGTI298/TRAIL 引起 IκBα 和 p-Akt 的减少，这表明 DR5 在由 GGTI298/TRAIL 导致的 IκBα 和 p-Akt 减少中起着关键作用。相比之下，敲除 DR4 进一步促进了 GGTI298/TRAIL 引起的 p-Akt 的减少。

体内研究

在活体小鼠回肠环实验中，TRAM-34、GGTI298 或 H1152 在与霍乱毒素一起注入回肠环后以剂量依赖性方式减少了液体积聚。

反应信息

• 作为产物：
  描述：

  2-溴-4-硝基苯甲酸甲酯 在 氢气 、 sodium cyanoborohydride 、 三氟乙酸 作用下， 生成 GGTI 298
  参考文献：
  名称：

  Selective inhibition of type-I geranylgeranyltransferase in vitro and in whole cells by CAAL peptidomimetics

  摘要：

  In this paper we describe the synthesis of a family of CAAL peptidomimetics as GGTase-I inhibitors. These inhibitors lack the central dipeptide AA in the key CAAL carboxy terminal sequence of geranylgeranylated proteins and are more selective for GGTase-I over FTase. In whole cells, these compounds are very potent inhibitors of the processing of the geranylgeranylated protein Rap1A without affecting the farnesylated protein H-Ras. One derivative, GGTI-298, inhibited cell division by blocking cells in the G(1) phase of the cell cycle. (C) 1998 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(97)10040-2

文献信息

• Mevalonate pathway inhibitor as highly-efficient vaccine adjuvant
  申请人：Tsinghua University

  公开号：US11382971B2

  公开（公告）日：2022-07-12

  Disclosed are inhibitors of mevalonate pathway as an efficient vaccine adjuvant and use thereof. In particular, the inhibitor is an acetoacetyl-CoA transferase inhibitor, a HMG-CoA synthase inhibitor, a HMG-CoA reductase inhibitor, a mevalonate kinase inhibitor, a phosphomevalonate kinase inhibitor, a mevalonate-5-pyrophosphate decarboxylase inhibitor, an isopentenyl pyrophosphate isomerase inhibitor, a farnesyl pyrophosphate synthase inhibitor, a geranylgeranyl pyrophosphate synthase inhibitor or a geranylgeranyl transferase (I, II) inhibitor. Also disclosed is an immunogenic composition comprising inhibitors of mevalonate pathway as an adjuvant.

  所公开的是作为高效疫苗佐剂的甲羟戊酸途径抑制剂及其用途。特别是，抑制剂是乙酰乙酰-CoA 转移酶抑制剂、HMG-CoA 合成酶抑制剂、HMG-CoA 还原酶抑制剂、甲羟戊酸激酶抑制剂、磷酸甲羟戊酸激酶抑制剂、甲羟戊酸-5-焦磷酸脱羧酶抑制剂、焦磷酸异戊烯酯异构酶抑制剂、焦磷酸法呢酯合成酶抑制剂、焦磷酸香叶酯合成酶抑制剂或香叶基香叶基转移酶 (I, II) 抑制剂。还公开了一种免疫原组合物，该组合物包含作为佐剂的甲羟戊酸途径抑制剂。
• Methods for Treating Cancer
  申请人：Kalyanaraman Balaraman

  公开号：US20070219208A1

  公开（公告）日：2007-09-20

  It is disclosed here that HMG-CoA reductase inhibitors inhibit the proliferation and cause the death of breast cancer cells by inducing the expression of inducible nitric oxide synthase (iNOS) to promote intracellular nitric oxide formation, which the inventors found to be accomplished through the inhibition of protein geranylgeranylation. The disclosure here enables a new breast cancer treatment strategy that combines the inhibition HMG-CoA reductase or protein geranylgeranylation and the promotion of nitric oxide formation by iNOS.
• PRENYLTRANSFERASE INHIBITORS FOR OCULAR HYPERTENSION CONTROL AND THE TREATMENT OF GLAUCOMA
  申请人：Shepard R. Allan

  公开号：US20070232675A1

  公开（公告）日：2007-10-04

  The invention concerns in one embodiment a method of treating glaucoma or elevated intraocular pressure comprising administering a pharmaceutically effective amount of a composition comprising at least one prenyltransferase inhibitor. In another embodiment, the invention concerns a composition for the treatment of elevated intraocular pressure and glaucoma comprising a pharmaceutically effective amount of a prenyltransferase inhibitor.
• METHODS FOR TREATING MACULAR EDEMA AND PATHOLOGIC OCULAR ANGIOGENESIS USING A NEUROPROTECTIVE AGENT AND A RECEPTOR TYROSINE KINASE INHIBITOR
  申请人：Bingaman David P.

  公开号：US20080153819A1

  公开（公告）日：2008-06-26

  The present invention provides methods for inhibiting increased vascular permeability and/or pathologic ocular angiogenesis and providing neuroprotection of the affected retina via administration of a combination of one or more molecules that potently inhibit select receptor tyrosine kinases (RTKs) or vascular endothelial growth factor (VEGF) and one or more neuroprotectants.
• PHARMACOLOGICAL TARGETING OF VASCULAR MALFORMATIONS
  申请人：Li Dean

  公开号：US20110112053A1

  公开（公告）日：2011-05-12

  Disclosed herein are compositions and methods for decreasing vascular permeability in a blood vessel and treating or preventing conditions associated with defects or injuries of vascular endothelium. For example, the disclosed compositions and methods can be used to treat a vascular dysplasia such as cerebral cavernous malformation (CCM). These methods relate generally to the use of compositions that inhibit RhoA GTPase levels or activity, such as inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.