Pexmetinib
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MedKoo CAT#: 200294

CAS#: 945614-12-0

Description: Pexmetinib, also known as ARRY-614, is an orally bioavailable small-molecule inhibitor of p38 and Tie2 kinases with potential antineoplastic, anti-inflammatory and antiangiogenic activities. p38/Tie2 kinase inhibitor Arry-614 binds to and inhibits the activities of p38 and Tie2 kinases, which may inhibit the production of proinflammatory cytokines and may decrease tumor angiogenesis and tumor cell growth and survival. p38 is a MAP kinase that is often upregulated in cancer cells, playing a crucial part in the production of a variety of cytokines involved in inflammation and cellular proliferation such as tumor necrosis factor (TNF) and interleukin (IL)-1 and -6. Tie2 is an endothelial cell specific receptor that is activated by angiopoietins, growth factors required for angiogenesis.


Chemical Structure

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Pexmetinib
CAS# 945614-12-0

Theoretical Analysis

MedKoo Cat#: 200294
Name: Pexmetinib
CAS#: 945614-12-0
Chemical Formula: C31H33FN6O3
Exact Mass: 556.26
Molecular Weight: 556.630
Elemental Analysis: C, 66.89; H, 5.98; F, 3.41; N, 15.10; O, 8.62

Price and Availability

Size Price Availability Quantity
5mg USD 150 Ready to ship
10mg USD 250 Ready to ship
25mg USD 450 Ready to ship
50mg USD 750 Ready to ship
100mg USD 1250 Ready to ship
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Synonym: ARRY614; ARRY-614; ARRY 614; Pexmetinib

IUPAC/Chemical Name: 1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(5-fluoro-2-((1-(2-hydroxyethyl)-1H-indazol-5-yl)oxy)benzyl)urea

InChi Key: LNMRSSIMGCDUTP-UHFFFAOYSA-N

InChi Code: InChI=1S/C31H33FN6O3/c1-20-5-8-24(9-6-20)38-29(17-28(36-38)31(2,3)4)35-30(40)33-18-22-15-23(32)7-12-27(22)41-25-10-11-26-21(16-25)19-34-37(26)13-14-39/h5-12,15-17,19,39H,13-14,18H2,1-4H3,(H2,33,35,40)

SMILES Code: O=C(NCC1=CC(F)=CC=C1OC2=CC3=C(N(CCO)N=C3)C=C2)NC4=CC(C(C)(C)C)=NN4C5=CC=C(C)C=C5

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

More Info:        

Biological target: Pexmetinib is a Tie-2 and p38 MAPK dual inhibitor, with IC50s of 1 nM, 35 nM and 26 nM for Tie-2, p38α and p38β, respectively.
In vitro activity: To determine the efficacy of pexmetinib in human hematopoietic cells, leukemic KG1 cells were treated with TNF-α with and without pexmetinib for indicated times and immunoblotted for phospho/activated p38 MAPK. TNF-α led to activation of p38 MAPK that was completely abrogated by pexmetinib treatment (Fig 6A). Downstream mediators of p38 MAPK, MAPKAPK2 and EIF4E were also evaluated by immunoblotting and pexmetinib was able to inhibit the activation of these effector kinases after TNF exposure. (Fig 6B,C). To assess the functional role of pexmetinib in human hematopoiesis, primary CD34+ stem cells were grown in methylcellulose media in the presence and absence of TNF-α (5ng/ml) and pexmetinib (0.1μM). Erythroid (BFU-E) and myeloid (CFU-GM) colonies were assessed after 14 days and revealed that TNF led myelosuppressive effects were significantly reversed by pexmetinib treatment (Fig 6D)(N=4, TTest, P Value<0.05). Finally, the effects of pexmetinib were assessed on leukemic cell proliferation and revealed the ability to significantly inhibit proliferation in vitro for two different AML derived cell lines (Fig 6E,F). Reference: Cancer Res. 2016 Aug 15; 76(16): 4841–4849. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398415/
In vivo activity: Due to similar protein binding between mouse and human plasma, this study was able to test this prediction by performing murine in vivo studies with HEK-Tie2 xenografts to assess the relationship between plasma concentration and target inhibition in lung (p-p38) or tumor (p-p38 and pTie-2). There was good concordance between plasma concentrations required to inhibit the p-p38 as assessed by immunoblot and the functional readout of LPS-induced TNFα, so data for this target were combined to generate an in vivo inhibitory value (Fig 5C). This study determined that murine plasma concentrations required to achieve 50% inhibition for pTie2 and p-p38 were 2066 nM and 203 nM, respectively, confirming that our predictions from protein binding-corrected in vitro inhibition were highly accurate. Reference: Cancer Res. 2016 Aug 15; 76(16): 4841–4849. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398415/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 30.0 53.90

Preparing Stock Solutions

The following data is based on the product molecular weight 556.63 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.

Recalculate based on batch purity %
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
Formulation protocol: 1. Bachegowda L, Morrone K, Winski SL, Mantzaris I, Bartenstein M, Ramachandra N, Giricz O, Sukrithan V, Nwankwo G, Shahnaz S, Bhagat T, Bhattacharyya S, Assal A, Shastri A, Gordon-Mitchell S, Pellagatti A, Boultwood J, Schinke C, Yu Y, Guha C, Rizzi J, Garrus J, Brown S, Wollenberg L, Hogeland G, Wright D, Munson M, Rodriguez M, Gross S, Chantry D, Zou Y, Platanias L, Burgess LE, Pradhan K, Steidl U, Verma A. Pexmetinib: A Novel Dual Inhibitor of Tie2 and p38 MAPK with Efficacy in Preclinical Models of Myelodysplastic Syndromes and Acute Myeloid Leukemia. Cancer Res. 2016 Aug 15;76(16):4841-4849. doi: 10.1158/0008-5472.CAN-15-3062. Epub 2016 Jun 10. PMID: 27287719; PMCID: PMC5398415.
In vitro protocol: 1. Bachegowda L, Morrone K, Winski SL, Mantzaris I, Bartenstein M, Ramachandra N, Giricz O, Sukrithan V, Nwankwo G, Shahnaz S, Bhagat T, Bhattacharyya S, Assal A, Shastri A, Gordon-Mitchell S, Pellagatti A, Boultwood J, Schinke C, Yu Y, Guha C, Rizzi J, Garrus J, Brown S, Wollenberg L, Hogeland G, Wright D, Munson M, Rodriguez M, Gross S, Chantry D, Zou Y, Platanias L, Burgess LE, Pradhan K, Steidl U, Verma A. Pexmetinib: A Novel Dual Inhibitor of Tie2 and p38 MAPK with Efficacy in Preclinical Models of Myelodysplastic Syndromes and Acute Myeloid Leukemia. Cancer Res. 2016 Aug 15;76(16):4841-4849. doi: 10.1158/0008-5472.CAN-15-3062. Epub 2016 Jun 10. PMID: 27287719; PMCID: PMC5398415.
In vivo protocol: 1. Bachegowda L, Morrone K, Winski SL, Mantzaris I, Bartenstein M, Ramachandra N, Giricz O, Sukrithan V, Nwankwo G, Shahnaz S, Bhagat T, Bhattacharyya S, Assal A, Shastri A, Gordon-Mitchell S, Pellagatti A, Boultwood J, Schinke C, Yu Y, Guha C, Rizzi J, Garrus J, Brown S, Wollenberg L, Hogeland G, Wright D, Munson M, Rodriguez M, Gross S, Chantry D, Zou Y, Platanias L, Burgess LE, Pradhan K, Steidl U, Verma A. Pexmetinib: A Novel Dual Inhibitor of Tie2 and p38 MAPK with Efficacy in Preclinical Models of Myelodysplastic Syndromes and Acute Myeloid Leukemia. Cancer Res. 2016 Aug 15;76(16):4841-4849. doi: 10.1158/0008-5472.CAN-15-3062. Epub 2016 Jun 10. PMID: 27287719; PMCID: PMC5398415.

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 1. Methods of using small compounds such as glatiramer acetate and mitogen activated protein (MAP) kinase inhibitors to enhance myeloid derived suppressor cell function for treating autoimmune diseases, By Chen, Shu-Hsia  From PCT Int. Appl. (2011), WO 2011087795 A2 20110721.