Wortmannin, Penicillium funiculosum

• CAT Number: I002494
• CAS Number: 19545-26-7
• Molecular Formula: C₂₃H₂₄O₈
• Molecular Weight: 428.44
• Purity: ≥95%
• Target: Autophagy
• Solubility: 10 mM in DMSO
• Storage: 3 years -20C powder
• IC50: 3 nM (PI3K) [1], 16 nM (DNA-PK) [2], 150 nM (ATM) [2], 170 nM (MLCK) [3]
• InChI: InChI=1S/C23H24O8/c1-10(24)30-13-7-22(2)12(5-6-14(22)25)16-18(13)23(3)15(9-28-4)31-21(27)11-8-29-20(17(11)23)19(16)26/h8,12-13,15H,5-7,9H2,1-4H3/t12-,13+,15+,22-,23-/m0/s1
• InChIKey: QDLHCMPXEPAAMD-QAIWCSMKSA-N
• SMILES: CC(=O)OC1CC2(C(CCC2=O)C3=C1C4(C(OC(=O)C5=COC(=C54)C3=O)COC)C)C

Wortmannin is a multi-target inhibitor of PI3K and MLCK with IC50 of 3 nM and 0.17 μM, respectively.IC50 value: 3 nM (PI3K) [1], 16 nM (DNA-PK) [2], 150 nM (ATM) [2], 170 nM (MLCK) [3]Target: PI3K, DNA-PK, ATM, MLCKIn vitro: The inhibition of MLCK by Wortmannin is not affected by calmodulin or peptide substrat, while reduced by high concentration of ATP. Wortmannin directly interacts with the catalytic domain of MLCK and leads to an irreversible loss of the enzyme activity. Wortmannin has no inhibitory to cAMP-dependent protein kinase, cGMP-dependent protein kinase, and calmodulin-dependent protein kinase II, and has little effect on protein kinase C activity.[3]Wortmannin irreversibly inhibits phosphatidylinositol 3-kinase (PI3-kinase) activity with binding to the 110-kDa protein (IC50 of 3 nM) and has no effect PI4-kinase in RBL-2H3 cells. Wortmannin also inhibits both Fc epsilon RI-mediated histamine secretion and leukotriene release, with no effect on the activation of the tyrosine kinase Lyn.[1]in vivo: Wortmannin inhibits phosphatidylinositide 3-kinase-protein kinase B (PKB)/Akt phosphorylation in both normal tissues (lung, heart and brain homogenates) and tumor tissue in mice, without mortality or acute toxicity at 0.7 mg/kg. Combination with LY188011, Wortmannin significantly increases apoptosis and inhibit tumor growth in orthotopic tumor, while both monotherapy could not.[4]

Reference

1:Enantioselective Total Synthesis of (+)-Wortmannin. Guo Y, Quan T, Lu Y, Luo T.J Am Chem Soc. 2017 May 11. doi: 10.1021/jacs.7b02515. [Epub ahead of print] PMID: 28474885 2:PI3K inhibitor LY294002, as opposed to wortmannin, enhances AKT phosphorylation in gemcitabine-resistant pancreatic cancer cells. Wang Y, Kuramitsu Y, Baron B, Kitagawa T, Tokuda K, Akada J, Maehara SI, Maehara Y, Nakamura K.Int J Oncol. 2017 Feb;50(2):606-612. doi: 10.3892/ijo.2016.3804. Epub 2016 Dec 14. PMID: 28000865 3:AKTs/PKBs: molecular characterization, tissue expression and transcriptional responses to insulin and/or wortmannin in yellow catfish Pelteobagrus fulvidraco. Zhuo MQ, Pan YX, Wu K, Xu YH, Zhang LH, Luo Z.Fish Physiol Biochem. 2017 Jun;43(3):719-730. doi: 10.1007/s10695-016-0327-y. Epub 2016 Dec 20. PMID: 28000079 4:Wortmannin-induced vacuole fusion enhances amyloplast dynamics in Arabidopsis zigzag1 hypocotyls. Alvarez AA, Han SW, Toyota M, Brillada C, Zheng J, Gilroy S, Rojas-Pierce M.J Exp Bot. 2016 Dec;67(22):6459-6472. Epub 2016 Nov 5. PMID: 27816929 Free PMC Article5:Profiling Kinase Activity during Hepatitis C Virus Replication Using a Wortmannin Probe. Desrochers GF, Sherratt AR, Blais DR, Nasheri N, Ning Z, Figeys D, Goto NK, Pezacki JP.ACS Infect Dis. 2015 Sep 11;1(9):443-52. doi: 10.1021/acsinfecdis.5b00083. Epub 2015 Aug 20. PMID: 27617927 6:Is Wortmannin-Induced Reorganization of the trans-Golgi Network the Key to Explain Charasome Formation? Foissner I, Sommer A, Hoeftberger M, Hoepflinger MC, Absolonova M.Front Plant Sci. 2016 Jun 3;7:756. doi: 10.3389/fpls.2016.00756. eCollection 2016. PMID: 27375631 Free PMC Article7:Wortmannin influences hypoxia-inducible factor-1 alpha expression and glycolysis in esophageal carcinoma cells. Zeng L, Zhou HY, Tang NN, Zhang WF, He GJ, Hao B, Feng YD, Zhu H.World J Gastroenterol. 2016 May 28;22(20):4868-80. doi: 10.3748/wjg.v22.i20.4868. PMID: 27239113 Free PMC Article8:CL316243 induces phosphatidylinositol 3,4,5-triphosphate production in rat adipocytes in an adenosine deaminase-, pertussis toxin-, or wortmannin-sensitive manner. Ohsaka Y, Nomura Y.Physiol Res. 2016 Jul 18;65(3):543-6. Epub 2016 Mar 15. PMID: 26988163 Free Article9:Investigating the Inhibitory Effect of Wortmannin in the Hotspot Mutation at Codon 1047 of PIK3CA Kinase Domain: A Molecular Docking and Molecular Dynamics Approach. Kumar DT, Doss CG.Adv Protein Chem Struct Biol. 2016;102:267-97. doi: 10.1016/bs.apcsb.2015.09.008. Epub 2015 Oct 29. Review. PMID: 26827608 10:Wortmannin, PI3K/Akt signaling pathway inhibitor, attenuates thyroid injury associated with severe acute pancreatitis in rats. Abliz A, Deng W, Sun R, Guo W, Zhao L, Wang W.Int J Clin Exp Pathol. 2015 Nov 1;8(11):13821-33. eCollection 2015. PMID: 26823696 Free PMC Article