A8544-5mg | Wortmannin [19545-26-7] Clinisciences

Background

Wortmannin is a selective and irreversible inhibitor of phosphatidylinositol-3-kinase with IC50 value of 1.9nM [1].

Wortmannin is a microbial product. It is produced by a fungal strain, Talaromyces wortmannin KY12420 and is screened out as a potent inhibitor of myosin light chain kina (MLCK). Wortmannin inhibits MLCK as directly interacting with the catalytic domain but not the calmodulin or the regulatory domains. It is found to be a non-competitive inhibitor. The IC50 value of wortmannin for MLCK is 1.9μM. Wortmannin inhibits the phosphorylation and contraction of myosin light chain in rat aort. As an inhibitor of MLCK, wortmannin is developed as vasodilators and anti-inflammatory agent [2].

Wortmannin is also found to be an inhibitor of PI3K with IC50 of 1.9nM in antiphosphotyrosine immunoprecipitates from Swiss 3T3 cells. The inhibition mode is noncompetitive with respect to ATP. Wortmannin is a highly selective inhibitor of PI3K. It has no inhibition effect on Ptdlns-4-kinase, protein kinase C, c-src protein tyrosine kinase and phosphoinositide-specific phospholipase C [1].

References:
[1] Powis G, Bonjouklian R, Berggren M M, et al. Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase. Cancer Research, 1994, 54(9): 2419-2423.
[2] Nakanishi S, Kakita S, Takahashi I, et al. Wortmannin, a microbial product inhibitor of myosin light chain kinase. Journal of Biological Chemistry, 1992, 267(4): 2157-2163.

Product Citation

1. Shuyi Chen, Yabiao Gao, et al. "Anti-cancer Drug Anlotinib Promotes Autophagy and Apoptosis in Breast Cancer." Front Biosci (Landmark Ed). 2022 Apr 7;27(4):125. PMID: 35468684
2. Wenli Yuan, Deyao Deng, et al. "IFNγ/PD-L1 Signaling Improves the Responsiveness of Anti-PD-1 Therapy in Colorectal Cancer: An in vitro Study." Onco Targets Ther. 2021 May 7;14:3051-3062. PMID: 33994797
3. Xia Li, Yuhan Zhang, et al. "Autophagy Activated by Peroxiredoxin of Entamoeba histolytica." Cells. 2020 Nov 12;9(11):2462. PMID: 33198056
4. Ming K, Yuan W, et al. "PI3KC3-dependent autophagosomes formation pathway is of crucial importance to anti-DHAV activity of Chrysanthemum indicum polysaccharide." Carbohydr Polym. 2019 Mar 15;208:22-31. PMID: 30658794
5. Yuan W, Deng D,et al."Hyperresponsiveness to interferon gamma exposure as a response mechanism to anti-PD-1 therapy in microsatellite instability colorectal cancer." Cancer Immunol Immunother. 2018 Nov 7. PMID: 30406373
6. Wang H, Liu W, et al. "Inhibitor analysis revealed that clathrin-mediated endocytosis is involed in cellular entry of type III grass carp reovirus." Virol J. 2018 May 24;15(1):92. PMID: 29793525
7. Jie Wu, Pingfan Guo, et al. "Glucagon-like peptide-1 affects human umbilical vein endothelial cells in high glucose by the PI3K/Akt/eNOS signaling pathway." Turk J Biochem. 2017 09 11.
8. Caster JM, Yu SK, et al. "Effect of particle size on the biodistribution, toxicity, and efficacy of drug-loaded polymeric nanoparticles in chemoradiotherapy." Nanomedicine. 2017 Mar 11. pii: S1549-9634(17)30044-8. PMID: 28300658

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Chemical Properties

Physical Appearance	A solid
Storage	Store at -20°C
M.Wt	428.43
Cas No.	19545-26-7
Formula	C₂₃H₂₄O₈
Solubility	≥21.42 mg/mL in DMSO; insoluble in H2O; insoluble in EtOH
Chemical Name	(1S,6bR,9aS,11R,11bR)-1-(methoxymethyl)-9a,11b-dimethyl-3,6,9-trioxo-3,6,6b,7,8,9,9a,10,11,11b-decahydro-1H-furo[4,3,2-de]indeno[4,5-h]isochromen-11-yl acetate
SDF	Download SDF
Canonical SMILES	O=C1[C@](C(17)(17)[C@@]2(17)OC(C(17)(17)17)=O)(C(17)(17)17)[C@](C(17)(17)C1(17)17)(17)C(C3=O)=C2[C@]4(C(17)(17)17)C5=C3OC(17)=C5C(O[C@]4(17)C(17)(17)OC(17)(17)17)=O
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Protocol

Cell experiment [1]:
Cell lines	v-sis NIH 3T3 cells
Preparation method	The solubility of this compound in DMSO is >21.4 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37°C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below - 20°C for several months.
Reacting condition	1.3 μM
Applications	In PDGF-stimulated v-sis NIH 3T3 cells, Wortmannin almost completely inhibited the formation of Ptdlns-3-phosphates. However, in resting cells, Wortmannin showed no effect on the pattern of phospholipids.
Animal experiment [2]:
Animal models	Immunodeficient mice bearing orthotopic human pancreatic cancer xenografts
Dosage form	0-0.7 mg/kg; i.v.; 0-4 hrs
Applications	In orthotopic human pancreatic cancer xenografts, PKB/Akt phosphorylation was inhibited by Wortmannin in a time- and dose-dependent manner, and reached a plateau at 4 hrs and at 0.7 mg/kg. Meanwhile, the levels of PKB/Akt phosphorylation were decreased maximally by ~50%.
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: [1]. Powis G, Bonjouklian R, Berggren M M, et al. Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase. Cancer Research, 1994, 54(9): 2419-2423. [2]. Ng SS, Tsao MS, Nicklee T, Hedley DW. Wortmannin inhibits pkb/akt phosphorylation and promotes gemcitabine antitumor activity in orthotopic human pancreatic cancer xenografts in immunodeficient mice. Clin Cancer Res. 2001 Oct;7(10):3269-75.

Biological Activity

Description	Wortmannin is an inhibitor of PI3K with an IC50 value of 3 nM.
Targets	PI3K	DNA-PK	ATM	MLCK	ATR
IC50	3 nM	16 nM	150 nM	170 nM	1.8 μM

Quality Control

Chemical structure

Related Biological Data

In Western blot assay, we test whether Wortmannin and 3-Me could inhibit the effect of autophagy in 3T3 cells. The 1mM of inhibitors can suppress the cell survival of 3T3 cells. Due to the death of cell at the high concentration of Wortmannin and 3-Me, they are not fit to test in Western blot assay. The result has been shown that the low concentration of Wortmannin and 3-Me (1μM) significantly enhanced the P62 and inhibited the level of autophagy in 3T3 cells.

Method:Western blot; Cell Lines:3T3 cell lines; Concentrations:1μM～1mM; Incubation Time:24 h.