WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 202172
Description: Mirdametinib, also known as PD-0325901, is a potent bioavailable and selective MEK inhibitor, which targets mitogen-activated protein kinase kinase (MAPK/ERK kinase or MEK) with potential antineoplastic activity. MEK inhibitor PD325901, a derivative of MEK inhibitor CI-1040, selectively binds to and inhibits MEK, which may result in the inhibition of the phosphorylation and activation of MAPK/ERK and the inhibition of tumor cell proliferation. The dual specific threonine/tyrosine kinase MEK is a key component of the RAS/RAF/MEK/ERK signaling pathway that is frequently activated in human tumors.
MedKoo Cat#: 202172
Chemical Formula: C16H14F3IN2O4
Exact Mass: 481.99503
Molecular Weight: 482.19
Elemental Analysis: C, 39.85; H, 2.93; F, 11.82; I, 26.32; N, 5.81; O, 13.27
Synonym: PD0325901; PD 0325901; PD-325901; mirdametinib
IUPAC/Chemical Name: (R)-N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide
InChi Key: SUDAHWBOROXANE-SECBINFHSA-N
InChi Code: InChI=1S/C16H14F3IN2O4/c17-11-3-2-10(16(25)22-26-7-9(24)6-23)15(14(11)19)21-13-4-1-8(20)5-12(13)18/h1-5,9,21,23-24H,6-7H2,(H,22,25)/t9-/m1/s1
SMILES Code: O=C(NOC[C@H](O)CO)C1=CC=C(F)C(F)=C1NC2=CC=C(I)C=C2F
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
|Biological target:||Mirdametinib (PD0325901) is a selective and non ATP-competitive MEK inhibitor with IC50 of 0.33 nM in cell-free assays, roughly 500-fold more potent than CI-1040 on phosphorylation of ERK1 and ERK2.|
|In vitro activity:||To assess the effects of PD0325901 on PTC cell growth, the GI50 was determined in PTC cell lines (TPC-1 and K2). Cells were treated in vitro with serial dilution of the PD0325901 ranging from 100 nmol/L to 0.0064 nmol/L. After 2 days of incubation with varying concentrations of PD0325901, cell growth was determined by MTT. The GI50 was 11 nmol/L for TPC-1 cells and 6.3 nmol/L for K2 cells, as determined by Prism software (Fig. 1A). After determining the GI50 of PD0325901 in PTC cells, PTC cells were treated with PD0325901 at three different concentrations (100, 10, or 1 nmol/L) for 4 days. After 4 days of treatment, results of the MTT assay indicated that PD0325901 suppressed the cell growth by 80% (P < 0.0001), 75% (P < 0.0001), and 27% (P = 0.0015) in K2 cells, and by 58% (P < 0.0001), 40% (P = 0.0002), and 26% (P = 0.0001) in TPC-1 cells, respectively (Fig. 1B). Both K2 and TPC-1 cells showed dose-dependent growth inhibition with PD0325901. These data showed that PD0325901 significantly inhibited the growth of PTC cells harboring a BRAF mutation at very low concentration (10 nmol/L) and only moderately reduced the growth of the PTC cells carrying the RET/PTC1 rearrangement at the same concentration. Reference: Mol Cancer Ther. 2010 Jul;9(7):1968-76. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20587665/|
|In vivo activity:||The inhibitory effects of PD0325901 were evaluated in vivo using a murine orthotopic xenograft model. PTC cells expressing luciferase were inoculated in situ into the right thyroid lobe of Ncr-nu/nu mice. A group of 10 mice was randomly selected after Xenogen luciferase bioimaging and used for treatment with vehicle, and 14 to 16 mice were used for the PD0325901 treatment group. One week after inoculation, PD0325901 was given to these mice (see Materials and Methods) for 3 weeks at 20 to 25 mg/kg. Tumor growth was monitored weekly by Xenogen luciferase bioimaging. Tumor sizes were measured and tumor volume was calculated if mice were sacrificed due to loss of 20% initial body weight or tumor burden. No tumors were detected by Xenogen in mice inoculated with K2 cells after 1 week of PD0325901 treatment, whereas mice treated with vehicle still showed intense luciferase expression (Fig. 3A). The treated mice remained tumor free during the 3-week treatment period (data not shown). At the end of 3 weeks, all mice inoculated with K2 and treated with vehicle were sacrificed with average tumor volume of 1,078.7 ± 285.3 mm3 (Fig. 3B). Tumor regression was apparent in 100% of mice harboring K2 tumors and treated with PD0325901, and therefore no mice in the treatment group died by 30 days due to tumor burden, whereas nearly 100% of mice treated with vehicle died within the same period (Fig. 3C). In mice inoculated with TPC-1 cells, the average tumor volume after 3 weeks of PD0325901 treatment was reduced by 58.3% (from 699 to 291.3 mm3; P = 0.0004) when compared with tumors from untreated (vehicle) mice (699 ± 241.8 mm3). In addition, the survival of the mice inoculated with TPC-1 cells was increased significantly compared with mice treated with vehicle (Fig. 3C). Median survival was 16 to 18 days in vehicle-treated animals and 30 to 33 days in PD0325901-treated mice (P = 0.00124). Similar to CI-1040, the solubility of PD0325901 remains an issue. The solubility of PD0325901 at pH 7 is only at 0.39 mg/mL. The poor solubility of PD0325901 resulted in a high percentage of censored deaths in mice inoculated with K2 cells (47–93%; Fig. 3C), although necropsy of these mice showed that no tumor was present in the thyroid. These data showed that PD0325901 suppressed tumor growth completely in mice inoculated with PTC cells carrying a BRAF mutation (K2) and significantly decreased tumor growth in mice inoculated with PTC cells carrying the RET/PTC1 rearrangement (TPC-1). Reference: Mol Cancer Ther. 2010 Jul;9(7):1968-76. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20587665/|
|Solvent||Max Conc. mg/mL||Max Conc. mM|
The following data is based on the product molecular weight 482.19 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
|Concentration / Solvent Volume / Mass||1 mg||5 mg||10 mg|
|1 mM||1.15 mL||5.76 mL||11.51 mL|
|5 mM||0.23 mL||1.15 mL||2.3 mL|
|10 mM||0.12 mL||0.58 mL||1.15 mL|
|50 mM||0.02 mL||0.12 mL||0.23 mL|
|In vitro protocol:||1. Henderson YC, Chen Y, Frederick MJ, Lai SY, Clayman GL. MEK inhibitor PD0325901 significantly reduces the growth of papillary thyroid carcinoma cells in vitro and in vivo. Mol Cancer Ther. 2010 Jul;9(7):1968-76. doi: 10.1158/1535-7163.MCT-10-0062. Epub 2010 Jun 29. PMID: 20587665; PMCID: PMC2935263. 2. Barrett SD, Bridges AJ, Dudley DT, Saltiel AR, Fergus JH, Flamme CM, Delaney AM, Kaufman M, LePage S, Leopold WR, Przybranowski SA, Sebolt-Leopold J, Van Becelaere K, Doherty AM, Kennedy RM, Marston D, Howard WA Jr, Smith Y, Warmus JS, Tecle H. The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901. Bioorg Med Chem Lett. 2008 Dec 15;18(24):6501-4. doi: 10.1016/j.bmcl.2008.10.054. Epub 2008 Oct 15. PMID: 18952427.|
|In vivo protocol:||1. Henderson YC, Chen Y, Frederick MJ, Lai SY, Clayman GL. MEK inhibitor PD0325901 significantly reduces the growth of papillary thyroid carcinoma cells in vitro and in vivo. Mol Cancer Ther. 2010 Jul;9(7):1968-76. doi: 10.1158/1535-7163.MCT-10-0062. Epub 2010 Jun 29. PMID: 20587665; PMCID: PMC2935263.|
1: Paulo JA, McAllister FE, Everley RA, Beausoleil SA, Banks AS, Gygi SP. Effects of MEK inhibitors GSK1120212 and PD0325901 in vivo using 10-plex quantitative proteomics and phosphoproteomics. Proteomics. 2014 Sep 5. doi: 10.1002/pmic.201400154. [Epub ahead of print] PubMed PMID: 25195567.
2: El-Hoss J, Cheng T, Carpenter EC, Sullivan K, Deo N, Mikulec K, Little DG, Schindeler A. A Combination of rhBMP-2 (Recombinant Human Bone Morphogenetic Protein-2) and MEK (MAP Kinase/ERK Kinase) Inhibitor PD0325901 Increases Bone Formation in a Murine Model of Neurofibromatosis Type I Pseudarthrosis. J Bone Joint Surg Am. 2014 Jul 16;96(14):e117. [Epub ahead of print] PubMed PMID: 25031379.
3: El-Hoss J, Kolind M, Jackson MT, Deo N, Mikulec K, McDonald MM, Little CB, Little DG, Schindeler A. Modulation of endochondral ossification by MEK inhibitors PD0325901 and AZD6244 (Selumetinib). Bone. 2014 Feb;59:151-61. doi: 10.1016/j.bone.2013.11.013. Epub 2013 Nov 20. PubMed PMID: 24269278.
4: Sheth PR, Liu Y, Hesson T, Zhao J, Vilenchik L, Liu YH, Mayhood TW, Le HV. Fully activated MEK1 exhibits compromised affinity for binding of allosteric inhibitors U0126 and PD0325901. Biochemistry. 2011 Sep 20;50(37):7964-76. doi: 10.1021/bi200542r. Epub 2011 Aug 26. PubMed PMID: 21793567.
5: Henderson YC, Chen Y, Frederick MJ, Lai SY, Clayman GL. MEK inhibitor PD0325901 significantly reduces the growth of papillary thyroid carcinoma cells in vitro and in vivo. Mol Cancer Ther. 2010 Jul;9(7):1968-76. doi: 10.1158/1535-7163.MCT-10-0062. Epub 2010 Jun 29. PubMed PMID: 20587665; PubMed Central PMCID: PMC2935263.
6: Hennig M, Yip-Schneider MT, Wentz S, Wu H, Hekmatyar SK, Klein P, Bansal N, Schmidt CM. Targeting mitogen-activated protein kinase kinase with the inhibitor PD0325901 decreases hepatocellular carcinoma growth in vitro and in mouse model systems. Hepatology. 2010 Apr;51(4):1218-25. doi: 10.1002/hep.23470. PubMed PMID: 20112426.
7: Huang W, Yang AH, Matsumoto D, Collette W, Marroquin L, Ko M, Aguirre S, Younis HS. PD0325901, a mitogen-activated protein kinase kinase inhibitor, produces ocular toxicity in a rabbit animal model of retinal vein occlusion. J Ocul Pharmacol Ther. 2009 Dec;25(6):519-30. doi: 10.1089/jop.2009.0060. PubMed PMID: 19929595.
8: Ciuffreda L, Del Bufalo D, Desideri M, Di Sanza C, Stoppacciaro A, Ricciardi MR, Chiaretti S, Tavolaro S, Benassi B, Bellacosa A, FoÃ R, Tafuri A, Cognetti F, Anichini A, Zupi G, Milella M. Growth-inhibitory and antiangiogenic activity of the MEK inhibitor PD0325901 in malignant melanoma with or without BRAF mutations. Neoplasia. 2009 Aug;11(8):720-31. PubMed PMID: 19649202; PubMed Central PMCID: PMC2713590.
9: Leyton J, Smith G, Lees M, Perumal M, Nguyen QD, Aigbirhio FI, Golovko O, He Q, Workman P, Aboagye EO. Noninvasive imaging of cell proliferation following mitogenic extracellular kinase inhibition by PD0325901. Mol Cancer Ther. 2008 Sep;7(9):3112-21. doi: 10.1158/1535-7163.MCT-08-0264. PubMed PMID: 18790789.
10: Liu D, Xing M. Potent inhibition of thyroid cancer cells by the MEK inhibitor PD0325901 and its potentiation by suppression of the PI3K and NF-kappaB pathways. Thyroid. 2008 Aug;18(8):853-64. doi: 10.1089/thy.2007.0357. PubMed PMID: 18651802; PubMed Central PMCID: PMC2857450.
11: Brown AP, Carlson TC, Loi CM, Graziano MJ. Pharmacodynamic and toxicokinetic evaluation of the novel MEK inhibitor, PD0325901, in the rat following oral and intravenous administration. Cancer Chemother Pharmacol. 2007 Apr;59(5):671-9. Epub 2006 Aug 31. PubMed PMID: 16944149.
Phase II clinical trials was published in 2010. The study propose was to evaluate the efficacy of mitogen-activated protein kinase/extracellular signal-related kinase kinase inhibitor PD-0325901 in advanced nonÂ–small cell lung cancer patients who had experienced treatment failure after, or were refractory to, standard systemic therapy. All patients had received prior systemic therapy (median of two regimens, including epidermal growth factor receptor inhibitors in 26%). Of 13 patients treated on schedule A, three discontinued due to adverse events (blurred vision, fatigue, and hallucinations, respectively). Twenty-one patients received schedule B. Main toxicities included diarrhea, fatigue, rash, vomiting, nausea, and reversible visual disturbances. Hematologic toxicity consisted mainly of mild-to-moderate anemia, without neutropenia. Chemistry abnormalities were rare. Mean (coefficient of variation) PD-0325901 trough plasma concentrations were 100 ng/mL (52%) and 173 ng/mL (73%) for schedules A and B, respectively, above the minimum target concentration established in preclinical studies (16.5 ng/mL). There were no objective responses. Seven patients had stable disease. Median (95% confidence interval) progression-free survival was 1.8 months (1.5-1.9) and overall survival was 7.8 months (4.5-13.9). Conclusions: PD-0325901 did not meet its primary efficacy end point. Future studies should focus on PD-0325901 schedule, rational combination strategies, and enrichment of patient selection based on mode of action. [source: Clin Cancer Res; 16(8); OF1Â–8 ].