Home > AMPK & > Dorsomorphin


Compound C,BML-275

Dorsomorphin是AMPK选择性抑制剂,Ki为109 nM,还能抑制ALK2,ALK3和ALK6。

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  • 生物活性

    Dorsomorphin is a potent, reversible, selective AMPK inhibitor with Ki of 109 nM in cell-free assays, exhibiting no significant inhibition of several structurally related kinases including ZAPK, SYK, PKCθ, PKA, and JAK3. Also inhibits type I BMP receptor activity. Dorsomorphin (Compound C; BML-275) is a potent cell-permeablereversible ATP-competitive inhibitor of AMPK and also used as a potent antigliomaagent.

    Kinase inhibition

    Compound C inhibits AMPK with Ki of 109 ± 16 nM in theabsence of AMP.[3]

  • 体外研究

  • 体内研究

  • 激酶实验

    AMPK Kinase Assay (ELISA Assay)[4]

    HT1080 cells were seeded in 24-well plates(2x104 cells per well) and treated with compound C in the presenceor absence of glucose or 10mM 2DG for 2 h. HT1080 cells that overexpressed thewild-type and dominant negative AMPKα1 were prepared by transfectingplasmid DNA (pAMPKα1-wt, pAMPKα1-D168A and pcFlag as a control) in 6-well plates, seeding in24-well plate and treating with UPR inhibitors. Cells were lysed with celllysis buffer (20mM Tris-HCl, pH 7.5, 250mM NaCl, 10% glycerol, 0.5% NP-40, 1 mMEDTA, 1 mM EGTA, 0.2 mM PMSF, 1 mg/mL pepstatin, 0.5mg/mL leupeptin, 5mM NaF,2mM Na3Vo4, 2mM β-glycerophosphate, 1mM DTT). Relative AMPK kinase activity (mean ± SD of duplicate determinations) to control sample (vehicle orpcFlag under normal growth conditions) was determined using the CycLex AMPKkinase assay kit according to the manufacturer’s instructions.

    CAP binding assay[5]

    Glioma cells were washed with cold PBS andlysed in NL buffer [50mmol/L HEPES-KOH (pH 7.5), 150mmol/L NaCl, 0.5% NP40,0.1mmol/L GDP, 2mmol/L Na3VO4, protease inhibitorcocktail, 1mmol/L EDTA, 10mmol/L β-glycerophosphate, and 50mmol/LNaF]. Protein lysates were incubated with 20 mL of (1:1) slurry of m7GDPagaroseat 4OC for 1 hour, washed four times with the lysis buffer,resuspended in Laemmli Sample Buffer, boiled, and resolved by SDS-PAGE. Thefollowing antibodies were used—phospho AMPKThr172, AMPK, AMPK b1/b12, phosphoACCSer79, ACC, phospho S6Ser235/236, phospho 4EBP1Thr37/46, 4EBP1, mTOR, phosphoAkt Ser473, phospho Akt Thr308, Akt, phospho Erk1/2Thr202/Tyr204, PARP, LC3,P62, actin, and tubulin. Detection was performed using anti-rabbit or antimousehorseradish peroxidase (HRP)–linked secondary antibodies followed bychemiluminescence.

  • 细胞实验


    The HepG2 cell lines were maintained inDulbecco’s modified Eagle’s medium (DMEM) containing 10% fetal bovine serum(FBS), 50 units/mL penicillin and 50μg/mL streptomycin, and cultured at 37°C ina humidified atmosphere with 5% CO2. For experiments, cells wereplated in plates for 2–3 d (i.e., 80% confluency) and serum starved overnightbefore treatments.


    Analysis Cell lysates were preparedaccording and separated on 7.5 or 12% gel electrophoresis. The proteins weretransferred to nitrocellulose membranes by electroblotting. The membranes wereblocked in 5% non-fat milk in phosphate-buffered saline (PBS), and incubatedwith the primary antibody at 4°C overnight and then with the secondary antibodyfor 1 h. After subsequent washes, the protein bands of interest were detected usingan enhanced chemiluminescence (ECL) system. Immunoblotting forβ-actinconfirmed equal loading of proteins. 

    RNAIsolation and Reverse Transcription Polymerase Chain Reaction (RT-PCR)

    Analysis RNA was isolated from cells usingTrizol according to the manufacturer’s instructions. cDNA was synthesized byusing an oligo(dT)16 primer and AccuPower RT premix. PCR was carriedout using an AccuPower PCR premix and a Thermal Cycler. Glyceraldehyde-3-phosphatedehydrogenase (GAPDH) was used as a control for the amount of total mRNA. Thefollowing primer pairs were used for PCR: human SESN2 5ʹ-CTC ACA CCA TTA AGCATG GAG-3ʹ (forward) and 5ʹ-CAA GCT CGG AAT TAA TGT GCC-3ʹ (reverse); and humanGAPDH 5ʹ-GAA GAT GGT GAT GGG ATT TC-3ʹ (forward) and 5ʹ-GAA GGT GAA GGT CGG AGTC-3ʹ (reverse).

  • 动物实验

    Tumor xenograft experiments[7]

    Six-week-old NOD/SCID nude mice weresubcutaneously inoculated with A549 or SMMC-7721 cells. Approximately 1x107 cells in 0.2 ml culture medium containing phosphate-buffered saline wereinjected subcutaneously into the right flank of the mice, which were thenobserved daily for signs of tumor development. Tumor volume was calculated asbelow: V (cm3)=width2 (cm2)x length (cm)/2.Seven days after inoculation, mice were randomly divided into two groups (n¼6).

    Intratumoral injection was performed to theexperimental group mice with 15 mg/kg compound C (compound C were dissolved inphysiological saline) twice weekly. The control group mice were treated bydirect intratumoral injection of physiological saline twice weekly.

  • 不同实验动物依据体表面积的等效剂量转换表(数据来源于FDA指南)

    动物 A (mg/kg) = 动物 B (mg/kg)×动物 B的Km系数/动物 AKm系数

    例如,已知某工具药用于小鼠的剂量为88 mg/kg , 则用于大鼠的剂量换算方法:将88 mg/kg 乘以小鼠的Km系数(3),再除以大鼠的Km系数(6),得到该药物用于大鼠的等效剂量44 mg/kg。

  • 参考文献

    [1] Kwon HJ, Kim GE, Lee YT, et al. Inhibition of platelet-derived growth factor receptor tyrosine kinase and downstream signaling pathways by Compound C. Cell Signal. 2013;25(4):883-897.
    [2] Bain J, Plater L, Elliott M, et al. The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007;408(3):297-315.
    [3] Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167-1174.

    ﹣20 ℃冷藏长期储存。冰袋运输
    4 mg/mL
    <1 mg/mL
    3 mg/mL


  • Clinical Trial Information ( data from http://clinicaltrials.gov )

    NCT Number Conditions Interventions Sponsor/Collaborators Phases Start Date Last Updated
    NCT01251562 Solid Tumors Drug: Sterile Compound c31510 for Injection Berg, LLC Phase 1 2011-01-01 2014-05-15
    NCT01607476 Alzheimer's Disease Drug: C11 PiB|Drug: F18 Flutametamol Mayo Clinic Phase 2 2012-07-01 2016-11-08
    NCT00811122 Alzheimer's Disease Radiation: 11C-PIB PET Scan|Radiation: FDG-PET Scan University of Utah Early Phase 1 2009-11-01 2016-08-09
    NCT01032031 Skin Cancer Dietary Supplement: Green tea + vitamin C high dose|Dietary Supplement: Placebo capsule University of Manchester|University of Leeds|University of Bradford 2009-03-01 2016-03-07
    NCT02689843 Polycystic Ovary Syndrome Drug: Cyproterone compound + Spironolactone|Drug: Metformin|Drug: Pioglitazone Shiraz University of Medical Sciences Early Phase 1 2016-03-01 2016-08-02
    NCT02093169 Healthy Men Drug: Part A: Lu AF35700|Drug: Part B: Lu AF35700 H. Lundbeck A/S Phase 1 2014-02-01 2014-09-22
    NCT00704990 Attention Deficit Hyperactivity Disorder Dietary Supplement: Zinc, Magnesium, Vitamin B6, Vitamin C (Compound Natural Health Product for ADHD) Kieran Cooley|The Canadian College of Naturopathic Medicine|University of Toronto|Centre for Addiction and Mental Health Phase 2|Phase 3 2008-09-01 2015-10-15
    NCT00866853 Hepatitis C|Viruses Drug: TMC435 Tibotec Pharmaceuticals, Ireland Phase 1 2009-03-01 2010-04-26
    NCT00175695 Pre-eclampsia Drug: Recombinant human activated protein C or drotrecogin alpha University of British Columbia Phase 2 2004-12-01 2011-02-03
    NCT00908414 HIV Infections Drug: TMC589337 40 mg|Drug: TMC589337 100 mg|Drug: TMC589337 200 mg|Drug: TMC589337 400 mg|Drug: TMC589354 40 mg|Drug: TMC589354 100 mg|Drug: TMC589354 200 mg|Drug: TMC589354 400 mg|Drug: TMC589337 AA mg|Drug: TMC589354 BB mg|Drug: TMC589337 CC mg|Drug: TMC589354 DD mg|Drug: TMC589337 EE mg|Drug: TMC589354 YY mg|Drug: TMC310911 300 mg|Drug: TMC310911 600 mg|Drug: Placebo Tibotec Pharmaceuticals, Ireland Phase 1 2009-05-01 2016-10-27
    NCT02410525 Healthy Drug: [11C]PF-06427878|Drug: PF-06427878 10 mg|Drug: PF-06427878 600 mg Pfizer Phase 1 2015-05-01 2015-10-27
    NCT01063946 Neoplasms, Malignant Drug: Ombrabulin (AVE8062) Sanofi Phase 1 2010-01-01 2011-12-20
    NCT01022229 Attention Deficit Hyperactivity Disorder Dietary Supplement: Compound Natural Health Product|Dietary Supplement: Placebo The Canadian College of Naturopathic Medicine|Health Canada|Centre for Addiction and Mental Health|SickKids Foundation Phase 3 2013-11-01 2016-01-27
    NCT02120664 Alzheimer's Disease Drug: Florbetapir (18F)|Drug: 11C-PiB Avid Radiopharmaceuticals Phase 1 2014-04-01 2017-01-20
    NCT02564562 Healthy Drug: [14C] PF-06463922 Pfizer Phase 1 2015-10-01 2015-12-03
    NCT02240290 N/A, as Healthy Volunteers Drug: tozadenant tablet|Drug: C14-tozadenant capsule Biotie Therapies Inc.|PRA Health Sciences|Tandem Labs|Xceleron Inc Phase 1 2013-09-01 2016-01-13
    NCT02448004 Healthy Drug: JNJ-63623872 Janssen Cilag N.V./S.A. Phase 1 2015-05-01 2016-07-07
    NCT02211885 Healthy Drug: 14C-BIRB 796 BS Boehringer Ingelheim Phase 1 2002-10-01 2014-08-07
    NCT01961505 Rheumatoid Arthritis Drug: Compound tripterygium gel|Drug: Placebo Guang'anmen Hospital of China Academy of Chinese Medical Sciences Phase 2|Phase 3 2011-10-01 2013-10-09
    NCT01723553 Atypical Alzheimers Disease|Logopenic Variant of Primary Progressive Aphasia (LPA)|Posterior Cortical Atrophy (PCA) Drug: C-11 PiB Mayo Clinic Phase 1 2012-11-01 2015-12-18
    NCT01663389 Infections, Bacterial Drug: GSK1322322 1000 mg containing radioactive 14C-GSK1322322|Drug: GSK1322322 1200 mg containing radioactive 14C-GSK1322322 GlaxoSmithKline Phase 1 2012-08-01 2016-11-18
    NCT00910884 Breast Cancer|Prostate Cancer|Sarcoma Other: laboratory biomarker analysis|Procedure: therapeutic dietary intervention Brabant Research Phase 1 2016-04-01 2015-07-20
    NCT01279603 Solid Tumors Drug: GO-203-2c Genus Oncology, LLC Phase 1 2011-01-01 2014-09-18
    NCT00085917 Hepatitis C|HIV Infections Drug: Double dose pegylated interferon with weight based Ribavirin|Drug: standard dose pegylated interferon alfa -2a and ribavirin National Institute of Allergy and Infectious Diseases (NIAID)|National Institutes of Health Clinical Center (CC) Phase 2 2004-06-01 2011-06-21


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