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MedKoo Cat#: 562180 | Name: EZM2302
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Description:

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

EZM2302, also known as GSK3359088, is a potent, selective, and orally available arginine methyltransferase CARM1 inhibitor.

Chemical Structure

EZM2302
EZM2302
CAS#1628830-21-6

Theoretical Analysis

MedKoo Cat#: 562180

Name: EZM2302

CAS#: 1628830-21-6

Chemical Formula: C29H37ClN6O5

Exact Mass: 584.2514

Molecular Weight: 585.10

Elemental Analysis: C, 59.53; H, 6.37; Cl, 6.06; N, 14.36; O, 13.67

Price and Availability

Size Price Availability Quantity
5mg USD 250.00 2 Weeks
10mg USD 450.00 2 Weeks
25mg USD 850.00 2 Weeks
50mg USD 1,350.00 2 Weeks
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Synonym
EZM2302; EZM-2302; EZM 2302; GSK3359088; GSK-3359088; GSK 3359088;
IUPAC/Chemical Name
Methyl (R)-2-(2-(2-chloro-5-(2-hydroxy-3-(methylamino)propoxy)phenyl)-6-(3,5-dimethylisoxazol-4-yl)-5-methylpyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate
InChi Key
OWCOTUVKROVONT-HXUWFJFHSA-N
InChi Code
InChI=1S/C29H37ClN6O5/c1-17-25(24-18(2)34-41-19(24)3)32-26(22-12-21(6-7-23(22)30)40-14-20(37)13-31-4)33-27(17)36-15-29(16-36)8-10-35(11-9-29)28(38)39-5/h6-7,12,20,31,37H,8-11,13-16H2,1-5H3/t20-/m1/s1
SMILES Code
O=C(N(CC1)CCC21CN(C3=NC(C4=CC(OC[C@H](O)CNC)=CC=C4Cl)=NC(C5=C(C)ON=C5C)=C3C)C2)OC
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
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
Product Data
Product Data
Certificate of Analysis
View CoA: current batch, Lot#C21M06C29
Safety Data Sheet (SDS)
View Safety Data Sheet (SDS)
Instruction
View handling instruction
Biological target:
EZM 2302 is an inhibitor of coactivator-associated arginine methyltransferase 1 (CARM1) with an IC50 of 6 nM.
In vitro activity:
To assess the cellular activity of EZM2302 in vitro, changes in cellular methylation levels upon treatment with CARM1 inhibitor were quantified. The effect of EZM2302 treatment on cellular methylation was tested by immunoblot in the multiple myeloma (MM) cell line RPMI-8226 (Fig. 3a, Supplementary Fig. S2). Methylation changes were measured at the well-characterized CARM1 substrates PABP1 and SmB. Ninety-six-hour EZM2302 treatment led to a concentration-dependent decrease in methylation of PABP1 (IC50 = 0.038 ± 0.015 µM, N = 3) and SmB (increased levels of SmBme0, EC50 = 0.018 ± 0.007 µM, N = 3), as well as in multiple aDMA bands (IC50 = 0.009 µM). Similar results were also observed in the NCI-H929 (Fig. 3b and Supplementary Fig. S2) and U266B1 MM cell lines (Supplementary Fig. S5,S6). The effects of CARM1 inhibition on cellular histone methylation at the putative CARM1 substrates H3R17 and H3R26 were also evaluated by performing western blot analysis on whole cell lysates. In summary, a novel series has been identified as CARM1 inhibitors. Multi-parametric chemical optimization resulted in compound EZM2302, which exhibited nanomolar biochemical activity against CARM1 that was well correlated with both cellular target engagement and in vitro anti-proliferative effect, and shows exquisite selectivity against other HMTs with no off-target activities. Reference: Sci Rep. 2017; 7: 17993. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740082/
In vivo activity:
A dose range-finding (DRF) study conducted for 7 days with twice daily (BID) oral dosing of EZM2302 in CB-17 SCID mice at 37.5–300 mg/kg showed that all doses were well-tolerated with minimal body weight loss (Supplementary Fig. S10). To understand the kinetics of in vivo target inhibition, levels of PABP1, SmB, and aDMA methylation were assessed in tumor tissue after 2, 4, and 8 days of EZM2302 treatment at 150 and 300 mg/kg BID, based on the tolerability of these doses in the DRF. Inhibition of PAPB1me2a and aDMA and induction of SmBme0 were robustly observed within two days of dosing, with maximal changes in methylation observed at day 4 in both dose groups (Fig. 4e and Supplementary Fig. S11). EZM2302 showed dose-dependent exposure and tumor growth inhibition (TGI) after 21 days in the RPMI-8226 xenograft model (Fig. 5a). Tumors in all EZM2302 dose groups measured on day 21 showed significant decreases in tumor growth compared to vehicle (2-way ANOVA compared to Vehicle, Dunnett’s post-test). Tumor growth inhibition ranged from 45% in the 37.5 mg/kg dose group to 63% in the 300 mg/kg dose group. RPMI-8226 xenograft tumors collected on day 21 showed a dose-dependent decrease in methylation at all tested CARM1 substrates (Fig. 5b,c and Supplementary Fig. S12). A statistically significant increase in unmethylated form of SmB (SmBme0) was detected at all dose groups, from an 8-fold increase at 37.5 mg/kg to a 14-fold increase at 150 mg/kg. aDMA levels were likewise significantly decreased at all dose groups, a maximal inhibition of 65% was observed at the 75 mg/kg dose group. In summary, EZM2302 is a tool compound that can be used to further explore the biological role of CARM1 and understand the role of this enzyme in multiple myeloma and other oncology indications. Reference: Sci Rep. 2017; 7: 17993. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740082/
Solvent mg/mL mM
Solubility
DMSO 91.0 155.53
DMSO 91.0 155.53
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 585.10 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. Drew AE, Moradei O, Jacques SL, Rioux N, Boriack-Sjodin AP, Allain C, Scott MP, Jin L, Raimondi A, Handler JL, Ott HM, Kruger RG, McCabe MT, Sneeringer C, Riera T, Shapiro G, Waters NJ, Mitchell LH, Duncan KW, Moyer MP, Copeland RA, Smith J, Chesworth R, Ribich SA. Identification of a CARM1 Inhibitor with Potent In Vitro and In Vivo Activity in Preclinical Models of Multiple Myeloma. Sci Rep. 2017 Dec 21;7(1):17993. doi: 10.1038/s41598-017-18446-z. PMID: 29269946; PMCID: PMC5740082.
In vitro protocol:
1. Drew AE, Moradei O, Jacques SL, Rioux N, Boriack-Sjodin AP, Allain C, Scott MP, Jin L, Raimondi A, Handler JL, Ott HM, Kruger RG, McCabe MT, Sneeringer C, Riera T, Shapiro G, Waters NJ, Mitchell LH, Duncan KW, Moyer MP, Copeland RA, Smith J, Chesworth R, Ribich SA. Identification of a CARM1 Inhibitor with Potent In Vitro and In Vivo Activity in Preclinical Models of Multiple Myeloma. Sci Rep. 2017 Dec 21;7(1):17993. doi: 10.1038/s41598-017-18446-z. PMID: 29269946; PMCID: PMC5740082.
In vivo protocol:
1. Drew AE, Moradei O, Jacques SL, Rioux N, Boriack-Sjodin AP, Allain C, Scott MP, Jin L, Raimondi A, Handler JL, Ott HM, Kruger RG, McCabe MT, Sneeringer C, Riera T, Shapiro G, Waters NJ, Mitchell LH, Duncan KW, Moyer MP, Copeland RA, Smith J, Chesworth R, Ribich SA. Identification of a CARM1 Inhibitor with Potent In Vitro and In Vivo Activity in Preclinical Models of Multiple Myeloma. Sci Rep. 2017 Dec 21;7(1):17993. doi: 10.1038/s41598-017-18446-z. PMID: 29269946; PMCID: PMC5740082.
1: Drew AE, Moradei O, Jacques SL, Rioux N, Boriack-Sjodin AP, Allain C, Scott MP, Jin L, Raimondi A, Handler JL, Ott HM, Kruger RG, McCabe MT, Sneeringer C, Riera T, Shapiro G, Waters NJ, Mitchell LH, Duncan KW, Moyer MP, Copeland RA, Smith J, Chesworth R, Ribich SA. Identification of a CARM1 Inhibitor with Potent In Vitro and In Vivo Activity in Preclinical Models of Multiple Myeloma. Sci Rep. 2017 Dec 21;7(1):17993. doi: 10.1038/s41598-017-18446-z. PubMed PMID: 29269946; PubMed Central PMCID: PMC5740082.