FR900359
(Synonyms: UBO-QIC) 目录号 : GC49089A cyclic depsipeptide and an inhibitor of Gαq, Gα11, and Gα14
Cas No.:107530-18-7
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
FR900359 is a cyclic depsipeptide that has been found in A. crenata and is an inhibitor of Gαq, Gα11, and Gα14 (IC50s = 13.18, 10.47, and 10 nM, respectively).1,2 It is selective for these Gα subunits over a panel of additional Gα subunits, including Gαs and Gαi, in bioluminescence resonance energy transfer (BRET) assays at 1 µM.3 FR900359 (1 µM) induces relaxation of precontracted isolated mouse tail arteries and inhibits platelet aggregation induced by U-46619 in washed isolated human platelets cultured with aspirin in a concentration-dependent manner.3,4 It induces cell cycle arrest at the G1 phase and reduces proliferation and serum-induced migration of B16 melanoma cells.3 FR900359 (2.5 µg/animal) inhibits airway hyperresponsiveness in a mouse model of house dust mite-induced allergic asthma.5
1.Fujioka, M., Koda, S., Morimoto, Y., et al.Structure of FR900359, a cyclic depsipeptide from Ardisia crenata simsJ. Org. Chem.53(12)2820-2825(1988) 2.Kukkonen, J.P.G-protein inhibition profile of the reported Gq/11 inhibitor UBO-QICBiochem. Biophys. Res. Commun.469(1)101-107(2016) 3.Schrage, R., Schmitz, A.-L., Gaffal, E., et al.The experimental power of FR900359 to study Gq-regulated biological processesNat. Commun.610156(2015) 4.Inamdar, V., Patel, A., Manne, B.J., et al.Characterization of UBO-QIC as a Gαq inhibitor in plateletsPlatelets26(8)771-778(2015) 5.Matthey, M., Roberts, R., Seidinger, A., et al.Targeted inhibition of Gq signaling induces airway relaxation in mouse models of asthmaSci. Transl. Med.9(407)eaag2288(2017)
| Cas No. | 107530-18-7 | SDF | |
| 别名 | UBO-QIC | ||
| Canonical SMILES | CCC(N[C@@H]([C@H](O)C(C)C)C(O[C@@H]([C@@]1([H])C(N([C@@](C(O[C@@H]([C@@H](C(O[C@@H](C(N(C(C(N[C@H](C(N([C@H](C(N1)=O)C)C)=O)C)=O)=C)C)=O)CC2=CC=CC=C2)=O)NC(C)=O)C(C)C)=O)([H])[C@@H](C)OC)C)=O)C(C)C)=O)=O | ||
| 分子式 | C49H75N7O15 | 分子量 | 1002.2 |
| 溶解度 | Chloroform: soluble | 储存条件 | -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 | 0.9978 mL | 4.989 mL | 9.978 mL |
| 5 mM | 0.1996 mL | 0.9978 mL | 1.9956 mL |
| 10 mM | 0.0998 mL | 0.4989 mL | 0.9978 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。
A Specialized Dehydrogenase Provides l-Phenyllactate for FR900359 Biosynthesis
Chembiochem 2022 May 18;23(10):e202100569.PMID:34846772DOI:10.1002/cbic.202100569.
d-Phenyllactate (PLA) is a component of the selective Gq protein inhibitor and nonribosomal cyclic depsipeptide FR900359 (FR). Here we report a detailed biochemical investigation of PLA biosynthesis and its incorporation into the natural product FR. The enzyme FrsC, member of the lactate/malate dehydrogenase superfamily, was shown to catalyze the formation of l-PLA from phenylpyruvate. FrsC was kinetically characterized and its substrate specificity determined. Incorporation of l-PLA was probed by assaying the adenylation domain FrsE-A3 and feeding studies with a Chromobacterium vaccinii ΔfrsC mutant, confirming preferred activation of l-PLA followed by on-line epimerization to d-PLA. Finally, detailed bioinformatic analyses of FrsC revealed its close relation to malate dehydrogenases from primary metabolism and suggest extensions in the substrate binding loop to be responsible for its adaptation to accepting larger aromatic substrates with high specificity.
Macrocyclic Gq Protein Inhibitors FR900359 and/or YM-254890-Fit for Translation?
ACS Pharmacol Transl Sci 2021 Feb 19;4(2):888-897.PMID:33860209DOI:10.1021/acsptsci.1c00021.
Guanine nucleotide-binding proteins (G proteins) transduce extracellular signals received by G protein-coupled receptors (GPCRs) to intracellular signaling cascades. While GPCRs represent the largest class of drug targets, G protein inhibition has only recently been recognized as a novel strategy for treating complex diseases such as asthma, inflammation, and cancer. The structurally similar macrocyclic depsipeptides FR900359 (FR) and YM-254890 (YM) are potent selective inhibitors of the Gq subfamily of G proteins. FR and YM differ in two positions, FR being more lipophilic than YM. Both compounds are utilized as pharmacological tools to block Gq proteins in vitro and in vivo. However, no detailed characterization of FR and YM has been performed, which is a prerequisite for the compounds' translation into clinical application. Here, we performed a thorough study of both compounds' physicochemical, pharmacokinetic, and pharmacological properties. Chemical stability was high across a large range of pH values, with FR being somewhat more stable than YM. Oral bioavailability and brain penetration of both depsipeptides were low. FR showed lower plasma protein binding and was metabolized significantly faster than YM by human and mouse liver microsomes. FR accumulated in lung after chronic intratracheal or intraperitoneal application, while YM was more distributed to other organs. Most strikingly, the previously observed longer residence time of FR resulted in a significantly prolonged pharmacologic effect as compared to YM in a methacholine-induced bronchoconstriction mouse model. These results prove that changes within a molecule which seem marginal compared to its structural complexity can lead to crucial pharmacological differences.
Delineation of molecular determinants for FR900359 inhibition of Gq/11 unlocks inhibition of Gαs
J Biol Chem 2020 Oct 2;295(40):13850-13861.PMID:32753482DOI:10.1074/jbc.RA120.013002.
Heterotrimeric G proteins are essential mediators of intracellular signaling of G protein-coupled receptors. The Gq/11 subfamily consists of Gq, G11, G14, and G16 proteins, of which all but G16 are inhibited by the structurally related natural products YM-254890 and FR900359. These inhibitors act by preventing the GDP/GTP exchange, which is necessary for activation of all G proteins. A homologous putative binding site for YM-254890/FR900359 can also be found in members of the other three G protein families, Gs, Gi/o, and G12/13, but none of the published analogs of YM-254890/FR900359 have shown any inhibitory activity for any of these. To explain why the YM-254890/FR900359 scaffold only inhibits Gq/11/14, the present study delineated the molecular selectivity determinants by exchanging amino acid residues in the YM-254890/FR900359-binding site in Gq and Gs We found that the activity of a Gs mutant with a Gq-like binding site for YM-254890/FR900359 can be inhibited by FR900359, and a minimum of three mutations are necessary to introduce inhibition in Gs In all, this suggests that although the YM-254890/FR900359 scaffold has proven unsuccessful to derive Gs, Gi/o, and G12/13 inhibitors, the mechanism of inhibition between families of G proteins is conserved, opening up the possibility of targeting by other, novel inhibitor scaffolds. In lack of a selective Gαs inhibitor, FR900359-sensitive Gαs mutants may prove useful in studies where delicate control over Gαs signaling would be of the essence.
Thioesterase-mediated side chain transesterification generates potent Gq signaling inhibitor FR900359
Nat Commun 2021 Jan 8;12(1):144.PMID:33420046DOI:10.1038/s41467-020-20418-3.
The potent and selective Gq protein inhibitor depsipeptide FR900359 (FR), originally discovered as the product of an uncultivable plant endosymbiont, is synthesized by a complex biosynthetic system comprising two nonribosomal peptide synthetase (NRPS) assembly lines. Here we characterize a cultivable bacterial FR producer, enabling detailed investigations into biosynthesis and attachment of the functionally important FR side chain. We reconstitute side chain assembly by the monomodular NRPS FrsA and the non-heme monooxygenase FrsH, and characterize intermolecular side chain transesterification to the final macrocyclic intermediate FR-Core, mediated by the FrsA thioesterase domain. We harness FrsA substrate promiscuity to generate FR analogs with altered side chains and demonstrate indispensability of the FR side chain for efficient Gq inhibition by comparative bioactivity, toxicity and docking studies. Finally, evolution of FR and side chain biosynthesis is discussed based on bioinformatics analyses. Side chain transesterification boosts potency and target affinity of selective Gq inhibitor natural products.
Vasorelaxant effect of FR900359 from Ardisia crenata on rat aortic artery
J Nat Med 2013 Jan;67(1):196-201.PMID:22388972DOI:10.1007/s11418-012-0644-0.
A cyclic depsipeptide, FR900359, isolated from Ardisia crenata was evaluated for vasorelaxant effects on rat aortic arteries. FR900359 caused concentration-dependent relaxation (1 nM-10 μM) in phenylephrine-precontracted endothelium-intact aortic rings, which was inhibited by addition of L-NMMA, a NOS inhibitor. In endothelium-denuded rings, the relaxant effect of low concentrations of FR900359 was diminished, but remained at high concentrations. In endothelium-denuded rings, FR900359 at 0.1 μM significantly attenuated high-K(+)-induced contractions and completely inhibited Ca(2+)-induced contractions. These results suggest that the vasorelaxant effect of FR900359 is mediated through the increased release of NO from endothelial cells at low concentrations, and can be attributed to inhibitory effects on voltage-dependent Ca(2+) channel- and receptor-operated Ca(2+) channel-dependent Ca(2+) influx at high concentrations.