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EZM0414 TFA (SETD2-IN-1 TFA) 2411759-92-5

EZM0414 TFA (SETD2-IN-1 TFA) 2411759-92-5

CAS No.: 2411759-92-5

EZM0414 TFA is a specific and orally bioactive inhibitor of the human histone methyltransferase SETD2. EZM0414 TFA has a
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EZM0414 TFA is a specific and orally bioactive inhibitor of the human histone methyltransferase SETD2. EZM0414 TFA has antiproliferation effects.

Physicochemical Properties


Molecular Formula C24H30F4N4O4
Molecular Weight 514.513020038605
Exact Mass 514.22
CAS # 2411759-92-5
Related CAS # EZM0414;2411748-50-8
PubChem CID 155971202
Appearance White to light yellow solid powder
Hydrogen Bond Donor Count 3
Hydrogen Bond Acceptor Count 9
Rotatable Bond Count 3
Heavy Atom Count 36
Complexity 693
Defined Atom Stereocenter Count 2
SMILES

FC1=CC=C(C)C2=C1C=C(C(N[C@@H]1CCC[C@@H](C1)N1CCN(C(C)=O)CC1)=O)N2.FC(C(=O)O)(F)F

InChi Key HASNOYOGMISGTP-PPPUBMIESA-N
InChi Code

InChI=1S/C22H29FN4O2.C2HF3O2/c1-14-6-7-19(23)18-13-20(25-21(14)18)22(29)24-16-4-3-5-17(12-16)27-10-8-26(9-11-27)15(2)28;3-2(4,5)1(6)7/h6-7,13,16-17,25H,3-5,8-12H2,1-2H3,(H,24,29);(H,6,7)/t16-,17+;/m1./s1
Chemical Name

N-[(1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl]-4-fluoro-7-methyl-1H-indole-2-carboxamide;2,2,2-trifluoroacetic acid
Synonyms

SETD2-IN-1 TFA; 2411759-92-5; SETD2-IN-1 (TFA); EZM0414 (TFA); N-[(1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl]-4-fluoro-7-methyl-1H-indole-2-carboxamide;2,2,2-trifluoroacetic acid; EZM0414 TFA; CHEMBL5303391;
HS Tariff Code 2934.99.9001
Storage

Powder-20°C 3 years

4°C 2 years

In solvent -80°C 6 months

-20°C 1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.
Shipping Condition Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity



Solubility Data



Molibresib (I-BET762; GSK-525762A) 1260907-17-2

Iadademstat (ORY-1001; RG6016) 2HCl 1431326-61-2

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Is for research use only, not for human use. We do not sell to patients.

Targets SETD2[1]
ln Vitro A panel of MM and DLBCL cell lines are inhibited by EZM0414, with an IC50 of 0.24 μM for t(4;14) cells and 0.023 μM->10 μM for DLBCL cell lines [2].
Inhibition of SETD2 by EZM0414 results in potent anti-proliferative effects in a panel of MM and DLBCL cell lines. EZM0414 inhibited proliferation in both t(4;14) and non-t(4;14) MM cell lines, with higher anti-proliferative activity generally observed in the t(4;14) subset of MM cell lines. The median IC 50value for EZM0414 in t(4;14) cell lines was 0.24 μM as compared to 1.2 μM for non-t(4;14) MM cell lines. Additionally, inhibitory growth effects on DLBCL cell lines demonstrated a wide range of sensitivity with IC 50 values from 0.023 μM to >10 μM. [2]
In vitro testing of EZM0414 in a safety panel consisting of 47 targets and a diversity panel of 72 kinases showed IC50 > 25 μM for all targets except D2 (IC50 = 13.0 μM, antagonist) and 5-HT1B (IC50 = 3.2 μM, agonist).[3]
ln Vivo In a NOD SCID mouse xenograft model implanted with human KMS-11 cells, EZM0414 (15 and 30 mg/kg, po, BID, daily) suppresses tumor growth and is well tolerated [3]. In rats and mice, EZM0414 (50 mg/kg, oral) has nearly 100% oral bioavailability, with t1/2 values of 1.8 hours for mice and 3.8 hours for rats [3].
EZM0414 resulted in statistically significant potent antitumor activity compared to the vehicle control in three MM and four DLBCL cell line-derived xenograft models. In the t(4;14) MM cell line-derived xenograft model, KMS-11, robust tumor growth regressions were observed at the top two doses with maximal TGI of 95%. In addition, two non-t(4;14) MM (RPMI-8226, MM.1S) and two DLBCL xenograft models (TMD8, KARPAS422) demonstrated > 75% TGI; with two additional DLBCL models (WSU-DLCL2, SU-DHL-10) exhibiting > 50% TGI in response to EZM0414. In all models tested, the antitumor effects observed correlated with reductions in intratumoral H3K36me3 levels demonstrating on-target inhibition of SETD2 methyltransferase activity in vivo. [2]
Enzyme Assay SETD2 (1434-1711) Assay [3]
The biochemical assay monitored the incorporation of the tritiated methyl group from S-adenosyl-methionine (SAM) into a biotinylated histone 3 peptide corresponding to residues 26-40. The sequence of the substrate peptide is biotin-Ahx-RKSAPATGGVKKPHR-NH2 and 3H-SAM was purchased from American Radiolabeled Chemicals, Inc. For the assay, 40 L of enzyme was incubated with 1 L of compound or DMSO for 30 minutes before initiating the reaction with 10 L of substrate solution in a 384- well assay plate. The assay was performed at room temperature in assay buffer composed of 25 mM bicine, pH 8.0, 7.5 mM -mercaptoethanol, 0.002 % Tween-20, and 0.01 % bovine skin gelatin (BSG). The reaction was quenched during the linear portion of product formation with 10 L of 1 mM S-adenosyl-homocysteine (SAH) and 1 mM SAM. From the quenched reaction, 50 L was transferred to a streptavidin-coated Flashplate (Perkin Elmer) and incubated for at least 2h before washing once with 0.1 % Tween-20. Signal from the 3H-labeled peptide captured by the streptavidin-coated plates was counted by a Topcount plate reader. Percent inhibition (%I) and IC50 values were calculated using equations 1 and 2 respectively. %
Solubility (In Vitro) DMSO : 200 mg/mL (388.72 mM)
H2O : 6.67 mg/mL (12.96 mM)
Solubility (In Vivo) Solubility in Formulation 1: ≥ 5 mg/mL (9.72 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.
Solubility in Formulation 2: ≥ 5 mg/mL (9.72 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Solubility in Formulation 3: ≥ 5 mg/mL (9.72 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.
 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 1.9436 mL 9.7180 mL 19.4360 mL
5 mM 0.3887 mL 1.9436 mL 3.8872 mL
10 mM 0.1944 mL 0.9718 mL 1.9436 mL
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.