IMP-1088
目录号 : GC40101An inhibitor of N-myristoyltransferase
Cas No.:2059148-82-0
Sample solution is provided at 25 µL, 10mM.
Quality Control & SDS
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- Purity: >95.00%
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- Datasheet
IMP-1088 is an inhibitor of N-myristoyltransferase 1 (NMT1) and NMT2 (IC50 = <1 nM for both human enzymes).[1] It inhibits replication of rhinovirus (RV), the virus most commonly responsible for the common cold, by inhibiting myristoylation of the RV capsid protein VP0 from strain RV-A16 in HeLa cells. IMP-1088 (500 nM) reduces RV-A16, RV-A1, RV-B14, and RV-A28 viral titers in HeLa cells without affecting cell growth (IC50 = >1,000 nM). It also blocks production of infectious RV-16 virus in primary human bronchial epithelial cells (hBECs) when added 3 hours post infection via inhibition of viral capsid assembly.
Reference:
1. Mousnier, A., Bell, A.S., Swieboda, D.P., et al. Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus. Nat. Chem. 10(6), 599-606 (2018).
| Cas No. | 2059148-82-0 | SDF | |
| 化学名 | 5-[3,4-difluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl]-N,N,1-trimethyl-1H-indazole-3-methanamine | ||
| Canonical SMILES | FC1=C(F)C=CC(C2=CC=C(N(C)N=C3CN(C)C)C3=C2)=C1OCCC4=C(C)N(C)N=C4C | ||
| 分子式 | C25H29F2N5O | 分子量 | 453.5 |
| 溶解度 | A solution in methyl acetate | 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 | 2.2051 mL | 11.0254 mL | 22.0507 mL |
| 5 mM | 0.441 mL | 2.2051 mL | 4.4101 mL |
| 10 mM | 0.2205 mL | 1.1025 mL | 2.2051 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。
Dual-Inhibition of Human N-Myristoyltransferase Subtypes Halts Common Cold Pathogenesis: Atomistic Perspectives from the Case of IMP-1088
Chem Biodivers 2022 Feb;19(2):e202100748.PMID:34936193DOI:10.1002/cbdv.202100748.
The pharmacological inhibition of human N-myristoyltransferase (HsNMT) has emerged as an efficient strategy to completely prevent the replication process of rhinoviruses, a potential treatment for the common cold. This was corroborated by the recent discovery of compound IMP-1088, a novel inhibitor that demonstrated a dual-inhibitory activity against the two HsNMT subtypes 1 and 2 without inducing cytotoxicity. However, the molecular and structural basis for the dual-inhibitory potential of IMP-1088 has not been investigated. As such, we employ molecular modelling techniques to resolve the structural mechanisms that account for the dual-inhibitory prowess of IMP-1088. Sequence and nanosecond-based analyses identified Tyr296, Phe190, Tyr420, Leu453, Gln496, Val181, Leu474, Glu182, and Asn246 as residues common within the binding pockets of both HsNMT1 and HsNMT2 subtypes whose consistent interactions with IMP-1088 underpin the basis for its dual inhibitory potency. Nano-second-based assessment of interaction dynamics revealed that Tyr296 consistently elicited high-affinity π-π stacked interaction with IMP-1088, thus further highlighting its cruciality corroborating previous report. An exploration of resulting structural changes upon IMP-1088 binding further revealed a characteristic impeding of residue fluctuations, structural compactness, and a consequential burial of crucial hydrophobic residues, features required for HsNMT1/2 functionality. Findings present essential structural perspectives that augment previous experimental efforts and could also advance drug development for treating respiratory tract infections, especially those mediated by rhinoviruses.
Inhibition of vaccinia virus L1 N-myristoylation by the host N-myristoyltransferase inhibitor IMP-1088 generates non-infectious virions defective in cell entry
PLoS Pathog 2022 Oct 10;18(10):e1010662.PMID:36215331DOI:10.1371/journal.ppat.1010662.
We have recently shown that the replication of rhinovirus, poliovirus and foot-and-mouth disease virus requires the co-translational N-myristoylation of viral proteins by human host cell N-myristoyltransferases (NMTs), and is inhibited by treatment with IMP-1088, an ultrapotent small molecule NMT inhibitor. Here, we examine the importance of N-myristoylation during vaccinia virus (VACV) infection in primate cells and demonstrate the anti-poxviral effects of IMP-1088. N-myristoylated proteins from VACV and the host were metabolically labelled with myristic acid alkyne during infection using quantitative chemical proteomics. We identified VACV proteins A16, G9 and L1 to be N-myristoylated. Treatment with NMT inhibitor IMP-1088 potently abrogated VACV infection, while VACV gene expression, DNA replication, morphogenesis and EV formation remained unaffected. Importantly, we observed that loss of N-myristoylation resulted in greatly reduced infectivity of assembled mature virus particles, characterized by significantly reduced host cell entry and a decline in membrane fusion activity of progeny virus. While the N-myristoylation of VACV entry proteins L1, A16 and G9 was inhibited by IMP-1088, mutational and genetic studies demonstrated that the N-myristoylation of L1 was the most critical for VACV entry. Given the significant genetic identity between VACV, monkeypox virus and variola virus L1 homologs, our data provides a basis for further investigating the role of N-myristoylation in poxviral infections as well as the potential of selective NMT inhibitors like IMP-1088 as broad-spectrum poxvirus inhibitors.
Validation and Invalidation of Chemical Probes for the Human N-myristoyltransferases
Cell Chem Biol 2019 Jun 20;26(6):892-900.e4.PMID:31006618DOI:10.1016/j.chembiol.2019.03.006.
On-target, cell-active chemical probes are of fundamental importance in chemical and cell biology, whereas poorly characterized probes often lead to invalid conclusions. Human N-myristoyltransferase (NMT) has attracted increasing interest as target in cancer and infectious diseases. Here we report an in-depth comparison of five compounds widely applied as human NMT inhibitors, using a combination of quantitative whole-proteome N-myristoylation profiling, biochemical enzyme assays, cytotoxicity, in-cell protein synthesis, and cell-cycle assays. We find that N-myristoylation is unaffected by 2-hydroxymyristic acid (100 μM), D-NMAPPD (30 μM), or Tris-DBA palladium (10 μM), with the latter compounds causing cytotoxicity through mechanisms unrelated to NMT. In contrast, drug-like inhibitors IMP-366 (DDD85646) and IMP-1088 delivered complete and specific inhibition of N-myristoylation in a range of cell lines at 1 μM and 100 nM, respectively. This study enables the selection of appropriate on-target probes for future studies and suggests the need for reassessment of previous studies that used off-target compounds.
Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus
Nat Chem 2018 Jun;10(6):599-606.PMID:29760414DOI:10.1038/s41557-018-0039-2.
Rhinoviruses (RVs) are the pathogens most often responsible for the common cold, and are a frequent cause of exacerbations in asthma, chronic obstructive pulmonary disease and cystic fibrosis. Here we report the discovery of IMP-1088, a picomolar dual inhibitor of the human N-myristoyltransferases NMT1 and NMT2, and use it to demonstrate that pharmacological inhibition of host-cell N-myristoylation rapidly and completely prevents rhinoviral replication without inducing cytotoxicity. The identification of cooperative binding between weak-binding fragments led to rapid inhibitor optimization through fragment reconstruction, structure-guided fragment linking and conformational control over linker geometry. We show that inhibition of the co-translational myristoylation of a specific virus-encoded protein (VP0) by IMP-1088 potently blocks a key step in viral capsid assembly, to deliver a low nanomolar antiviral activity against multiple RV strains, poliovirus and foot and-mouth disease virus, and protection of cells against virus-induced killing, highlighting the potential of host myristoylation as a drug target in picornaviral infections.