GSM-1
目录号 : GC62998
GSM-1 是有效的 γ-secretase 调节剂。GSM-1 直接靶向早衰蛋白 1 (PS1) 的跨膜结构域。
Cas No.:884600-68-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
GSM-1 is a potent γ-secretase modulator. GSM-1 directly targets the transmembrane domain (TMD) 1 of presenilin 1 (PS1)[1][2].
GSM-1 increases the levels of Aβ38 produced from WT APP. GSM-1 potently loweres the levels of Aβ42 of WT APP and all the Phe mutants by ∼70-80%, even for the V44F mutant, which produced only extremely small amounts of Aβ42[1].GSM-1 directly binds to the N-terminal fragment of PS1[2].
[1]. Richard M, et al. Beta-amyloid Precursor Protein Mutants Respond to Gamma-Secretase Modulators. J Biol Chem. 2010 Jun 4;285(23):17798-810.
[2]. Yu Ohki, et al. Phenylpiperidine-type γ-secretase Modulators Target the Transmembrane Domain 1 of Presenilin 1. EMBO J. 2011 Oct 14;30(23):4815-24.
| Cas No. | 884600-68-4 | SDF | |
| 分子式 | C26H31ClF3NO2 | 分子量 | 481.98 |
| 溶解度 | DMSO : 100 mg/mL (207.48 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
| 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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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.0748 mL | 10.3739 mL | 20.7477 mL |
| 5 mM | 0.415 mL | 2.0748 mL | 4.1495 mL |
| 10 mM | 0.2075 mL | 1.0374 mL | 2.0748 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 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 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
γ-Secretase modulator (GSM) photoaffinity probes reveal distinct allosteric binding sites on presenilin
J Biol Chem 2013 Apr 5;288(14):9710-9720.PMID:23396974DOI:10.1074/jbc.M112.398602.
γ-Secretase is an intramembrane aspartyl protease that cleaves the amyloid precursor protein to produce neurotoxic β-amyloid peptides (i.e. Aβ42) that have been implicated in the pathogenesis of Alzheimer disease. Small molecule γ-secretase modulators (GSMs) have emerged as potential disease-modifying treatments for Alzheimer disease because they reduce the formation of Aβ42 while not blocking the processing of γ-secretase substrates. We developed clickable GSM photoaffinity probes with the goal of identifying the target of various classes of GSMs and to better understand their mechanism of action. Here, we demonstrate that the photoaffinity probe E2012-BPyne specifically labels the N-terminal fragment of presenilin-1 (PS1-NTF) in cell membranes as well as in live cells and primary neuronal cultures. The labeling is competed in the presence of the parent imidazole GSM E2012, but not with acid GSM-1, allosteric GSI BMS-708163, or substrate docking site peptide inhibitor pep11, providing evidence that these compounds have distinct binding sites. Surprisingly, we found that the cross-linking of E2012-BPyne to PS1-NTF is significantly enhanced in the presence of the active site-directed GSI L-685,458 (L458). In contrast, L458 does not affect the labeling of the acid GSM photoprobe GSM-5. We also observed that E2012-BPyne specifically labels PS1-NTF (active γ-secretase) but not full-length PS1 (inactive γ-secretase) in ANP.24 cells. Taken together, our results support the hypothesis that multiple binding sites within the γ-secretase complex exist, each of which may contribute to different modes of modulatory action. Furthermore, the enhancement of PS1-NTF labeling by E2012-BPyne in the presence of L458 suggests a degree of cooperativity between the active site of γ-secretase and the modulatory binding site of certain GSMs.
Phenylpiperidine-type γ-secretase modulators target the transmembrane domain 1 of presenilin 1
EMBO J 2011 Oct 14;30(23):4815-24.PMID:22002539DOI:10.1038/emboj.2011.372.
Amyloid-β peptide ending at the 42nd residue (Aβ42) is implicated in the pathogenesis of Alzheimer's disease (AD). Small compounds that exhibit selective lowering effects on Aβ42 production are termed γ-secretase modulators (GSMs) and are deemed as promising therapeutic agents against AD, although the molecular target as well as the mechanism of action remains controversial. Here, we show that a phenylpiperidine-type compound GSM-1 directly targets the transmembrane domain (TMD) 1 of presenilin 1 (PS1) by photoaffinity labelling experiments combined with limited digestion. Binding of GSM-1 affected the structure of the initial substrate binding and the catalytic sites of the γ-secretase, thereby decreasing production of Aβ42, possibly by enhancing its conversion to Aβ38. These data indicate an allosteric action of GSM-1 by directly binding to the TMD1 of PS1, pinpointing the target structure of the phenylpiperidine-type GSMs.
Modulation of Aβ42 in vivo by γ-secretase modulator in primates and humans
Alzheimers Res Ther 2015 Aug 5;7(1):55.PMID:26244059DOI:10.1186/s13195-015-0137-y.
Introduction: Ibuprofen is one of the nonsteroidal anti-inflammatory drugs that have been shown to selectively lower pathogenic amyloid beta-peptide (Aβ)42 without impairing overall γ-secretase activity in vitro. This γ-secretase modulator (GSM) activity has been hypothesized to contribute to the reduction in risk of developing Alzheimer's disease in chronic users of nonsteroidal anti-inflammatory drugs. However, it is unclear whether ibuprofen, within therapeutic dosing range, demonstrates GSM activity in humans. In this study, we evaluated the effects of ibuprofen and a second-generation GSM, GSM-1, on Aβ levels in cerebrospinal fluid and plasma of young nonhuman primates and humans. Methods: Five to seven conscious cynomolgus monkeys (Macaca fascicularis) were nontreated or treated with 30 mg/kg GSM-1 or 50 or 100 mg/kg ibuprofen and the plasma and cerebrospinal fluid were sampled at -8, 0 (baseline or right before treatment), 2, 4, 6, 8, 12, and 24 h postdosing. In addition, sixteen healthy human subjects were randomly assigned to receive either placebo or 800 mg ibuprofen given by intravenous administration and plasma were collected at 0 (before drug infusion), 0.5, 1, 2, 4, 6, 8, 10, and 24 h after dosing. Results: A single dose of GSM-1 (30 mg/kg) decreased the ratio of Aβ42 to Aβ40 to 60% in plasma and the ratio of Aβ42 to total Aβ to 65% in cerebrospinal fluid from baseline to postdosing in monkeys. However, no significant changes were detected following ibuprofen treatment at 100 mg/kg. Consistent with the results from nonhuman primates, ibuprofen did not alter plasma Aβ levels in human volunteers after a single 800 mg dose. Conclusions: GSM-1 exerted potent lowering of the ratio of Aβ42 to Aβ40 in nonhuman primates but the hypothesized GSM activity of ibuprofen could not be demonstrated in nonhuman primates and humans after acute dosing.
Piperidine acetic acid based γ-secretase modulators directly bind to Presenilin-1
ACS Chem Neurosci 2011 Dec 21;2(12):705-710.PMID:22229075DOI:10.1021/cn200098p.
Aβ42 is believed to play a causative role in Alzheimer's disease (AD) pathogenesis. γ-Secretase modulators (GSMs) are actively being pursued as potential AD therapeutics because they selectively alter the cleavage site of the amyloid precursor protein (APP) to reduce the formation of Aβ42. However, the binding partner of acid based GSMs was unresolved until now. We have developed clickable photoaffinity probes based on piperidine acetic acid GSM-1 and identified PS1 as the target within the γ-secretase complex. Furthermore, we provide evidence that allosteric interaction of GSMs with PS1 results in a conformational change in the active site of the γ-secretase complex leading to the observed modulation of γ-secretase activity.
A Local Desymmetrization Approach to Piperidinyl Acetic Acid γ-Secretase Modulators
J Org Chem 2021 Nov 5;86(21):15481-15487.PMID:34641679DOI:10.1021/acs.joc.1c01970.
A desymmetrization-based approach for the synthesis of piperidinyl acetic acid γ-secretase modulators has been developed. The synthetic sequence features the use of N-tert-butanesulfinyl imine reduction and a diastereoselective lactam formation to set up the chiral centers. The synthetic utility is demonstrated by the concise asymmetric synthesis of γ-secretase modulator GSM-1.