Pexmetinib free base | CAS#1073667-64-7 | p38 MARK inhibitor

MedKoo Cat#: 200294 | Name: Pexmetinib

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Pexmetinib (ARRY-614) is an orally bioavailable, dual inhibitor of p38 MAPK (mitogen-activated protein kinase) and Tie2 (tyrosine kinase with immunoglobulin-like and EGF-like domains 2), developed primarily for treating myelodysplastic syndromes (MDS). In preclinical studies, pexmetinib potently inhibits p38α with an IC₅₀ of ~11 nM and Tie2 with an IC₅₀ of ~14 nM, effectively blocking proinflammatory cytokine production and modulating hematopoietic signaling.

Chemical Structure

Pexmetinib

CAS#945614-12-0 (free base)

Theoretical Analysis

MedKoo Cat#: 200294

Name: Pexmetinib

CAS#: 945614-12-0 (free base)

Chemical Formula: C31H33FN6O3

Exact Mass: 556.2598

Molecular Weight: 556.63

Elemental Analysis: C, 66.89; H, 5.98; F, 3.41; N, 15.10; O, 8.62

Price and Availability

Size	Price	Availability
5mg	USD 150.00	Ready to ship
10mg	USD 250.00	Ready to ship
25mg	USD 450.00	Ready to ship
50mg	USD 750.00	Ready to ship
100mg	USD 1,250.00	Ready to ship

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Related CAS #

945614-12-0 (free base) 1416216-01-7 (HCl)

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

In a Phase I clinical trial in lower-risk MDS patients, pexmetinib showed hematologic improvements in ~32% of evaluable patients, with reductions in bone marrow blast counts and inflammatory cytokine levels (notably TNF-α and IL-6). The drug was generally well tolerated, with manageable adverse effects such as fatigue and gastrointestinal symptoms. Overall, pexmetinib demonstrates promising bioactivity by targeting both inflammatory and angiogenic signaling pathways implicated in MDS pathogenesis.

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#T20D12P08

QC Data

View QC data: current batch, Lot#T20D12P08

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

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/

	Solvent	mg/mL	mM
Solubility
	DMSO	30.0	53.90

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

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.

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:

In vivo protocol:

1: Fontana D, Malighetti F, Villa M, Zambon A, Gambacorti-Passerini C, Mologni L. Repurposing pexmetinib as an inhibitor of TKI-resistant BCR::ABL1. Leukemia. 2024 Aug;38(8):1843-1847. doi: 10.1038/s41375-024-02282-y. Epub 2024 May 15. PMID: 38750137; PMCID: PMC11286508. 2: Sun X, Wu Y, Xu F, Liu C. Screening of potent RIPK3 inhibitors to attenuate necroptosis and inflammation in mouse traumatic brain injury models. Exp Neurol. 2024 Feb;372:114633. doi: 10.1016/j.expneurol.2023.114633. Epub 2023 Dec 5. PMID: 38061556. 3: Luke JJ, Dadey RE, Augustin RC, Newman S, Singh KB, Doerfler R, Behr S, Lee P, Isett B, Deitrick C, Li A, Joy M, Reeder C, Smith K, Urban J, Sellitto L, Jelinek M, Christner SM, Beumer JH, Villaruz LC, Kulkarni A, Davar D, Poklepovic AS, Najjar Y, Zandberg DP, Soloff AC, Bruno TC, Vujanović L, Skinner HD, Ferris RL, Bao R. Tumor cell p38 inhibition to overcome immunotherapy resistance. Res Sq [Preprint]. 2023 Aug 19:rs.3.rs-3183496. doi: 10.21203/rs.3.rs-3183496/v1. PMID: 37645831; PMCID: PMC10462255. 4: Jie Z, Wang S, Ma Q, Shen Y, Zhao X, Yu H, Xie Z, Jiang C. Pexmetinib suppresses osteoclast formation and breast cancer induced osteolysis via P38/STAT3 signal pathway. J Bone Oncol. 2022 Jun 11;35:100439. doi: 10.1016/j.jbo.2022.100439. PMID: 35800294; PMCID: PMC9253705. 5: Su H, Jiang M, Senevirathne C, Aluri S, Zhang T, Guo H, Xavier-Ferrucio J, Jin S, Tran NT, Liu SM, Sun CW, Zhu Y, Zhao Q, Chen Y, Cable L, Shen Y, Liu J, Qu CK, Han X, Klug CA, Bhatia R, Chen Y, Nimer SD, Zheng YG, Iancu-Rubin C, Jin J, Deng H, Krause DS, Xiang J, Verma A, Luo M, Zhao X. Methylation of dual- specificity phosphatase 4 controls cell differentiation. Cell Rep. 2021 Jul 27;36(4):109421. doi: 10.1016/j.celrep.2021.109421. PMID: 34320342; PMCID: PMC9110119. 6: Hou H, Ning F, Zhang JY, Lu Q, Zhang M, Wu P, Chen M, Lash GE. Angiopoietin 2 stimulates trophoblast invasion via a mechanism associated with JNK signaling. Mol Hum Reprod. 2021 Feb 27;27(3):gaab014. doi: 10.1093/molehr/gaab014. PMID: 33629098. 7: 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. 8: Wollenberg LA, Corson DT, Nugent CA, Peterson FL, Ptaszynski AM, Arrigo A, Mannila CG, Litwiler KS, Bell SJ. An exploratory, randomized, parallel-group, open-label, relative bioavailability study with an additional two-period crossover food-effect study exploring the pharmacokinetics of two novel formulations of pexmetinib (ARRY-614). Clin Pharmacol. 2015 Sep 30;7:87-95. doi: 10.2147/CPAA.S83871. PMID: 26491375; PMCID: PMC4598228. 9: Gañán-Gómez I, Bohannan ZS, Garcia-Manero G. p38 MAPK in MDS. Aging (Albany NY). 2015 Jun;7(6):346-7. doi: 10.18632/aging.100757. PMID: 26081220; PMCID: PMC4505155. 10: Garcia-Manero G, Khoury HJ, Jabbour E, Lancet J, Winski SL, Cable L, Rush S, Maloney L, Hogeland G, Ptaszynski M, Calvo MC, Bohannan Z, List A, Kantarjian H, Komrokji R. A phase I study of oral ARRY-614, a p38 MAPK/Tie2 dual inhibitor, in patients with low or intermediate-1 risk myelodysplastic syndromes. Clin Cancer Res. 2015 Mar 1;21(5):985-94. doi: 10.1158/1078-0432.CCR-14-1765. Epub 2014 Dec 5. PMID: 25480830; PMCID: PMC4348327. 11: Bachegowda L, Gligich O, Mantzaris I, Schinke C, Wyville D, Carrillo T, Braunschweig I, Steidl U, Verma A. Signal transduction inhibitors in treatment of myelodysplastic syndromes. J Hematol Oncol. 2013 Jul 10;6:50. doi: 10.1186/1756-8722-6-50. PMID: 23841999; PMCID: PMC3716523.