WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H407134
CAS#: 1598383-40-4
Description: EPZ011989 is a potent, orally-available EZH2 inhibitor with robust in vivo activity. EPZ011989 demonstrates significant tumor growth inhibition in a mouse xenograft model of human B cell lymphoma. EPZ011989 represents a powerful tool for the expanded exploration of EZH2 activity in biology. Inhibitors of the protein methyltransferase Enhancer of Zeste Homolog 2 (EZH2) may have significant therapeutic potential for the treatment of B cell lymphomas and other cancer indications. The ability of the scientific community to explore fully the spectrum of EZH2-associated pathobiology has been hampered by the lack of in vivo-active tool compounds for this enzyme.
Hodoodo Cat#: H407134
Name: EPZ011989
CAS#: 1598383-40-4
Chemical Formula: C35H51N5O4
Exact Mass: 605.39
Molecular Weight: 605.820
Elemental Analysis: C, 69.39; H, 8.49; N, 11.56; O, 10.56
Synonym: EPZ011989; EPZ-011989; EPZ 011989.
IUPAC/Chemical Name: N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl((1r,4r)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)amino)-2-methyl-5-(3-morpholinoprop-1-yn-1-yl)benzamide
InChi Key: XQFINGFCBFHOPE-WXUXXXNLSA-N
InChi Code: InChI=1S/C35H51N5O4/c1-7-40(30-12-10-29(11-13-30)38(5)15-18-43-6)33-23-28(9-8-14-39-16-19-44-20-17-39)22-31(27(33)4)34(41)36-24-32-25(2)21-26(3)37-35(32)42/h21-23,29-30H,7,10-20,24H2,1-6H3,(H,36,41)(H,37,42)/t29-,30-
SMILES Code: O=C(NCC1=C(C)C=C(C)NC1=O)C2=CC(C#CCN3CCOCC3)=CC(N(CC)[C@H]4CC[C@H](N(CCOC)C)CC4)=C2C
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: | EPZ011989 is a potent, selective orally bioavailable EZH2 inhibitor with IC50 value: < 3 nM ( Ki for wt EZH2, EZH2 Y646). |
| In vitro activity: | To rescue SLFN11 expression in 361-PBDr cells, the cells were cultured in the presence of 10 μmol/L of the EZH2 inhibitor, EPZ011989 (EPZ) for 10 days. Significantly increased SLFN11 expression was observed (Fig. 4A) and EPZ-treated cells showed increased sensitivity to SG3199 and MEDI0641 (Fig. 4B). To strengthen the findings in the 361-PBDr cells, the effect of SLFN11 derepression with EPZ on cell lines shown to have SLFN11 deficiency was investigated. Treatment with 5 μmol/L EPZ for 5 or 10 days rescued SLFN11 expression in K562 chronic myeloid leukemia cells and NCI-H82 lung cancer cells, respectively, and enhancement of SG3199 sensitivity was observed (Fig. 4D). Taken together, these data suggest that SLFN11 expression can be regulated via histone methylation in those cells, and downregulated SLFN11 is at least partially contributing to the development of PBD resistance in 361-PBDr cells. Reference: Mol Cancer Ther. 2021 Mar; 20(3): 541-552. https://mct.aacrjournals.org/content/20/3/541.long |
| In vivo activity: | To demonstrate further the utility of EPZ011989 as an in vivo tool compound, the antitumor activity of the optimized d-tartrate (DTAL) salt form in the treatment of subcutaneous EZH2 mutant KARPAS-422 human DLBCL xenografts was evaluated. Homogenous suspensions of 250 and 500 mg/kg in 0.5% methyl cellulose and 0.1% Tween-80 were dosed orally to implanted SCID mice for 21 days, BID (twice-daily). EPZ011989 administration induced significant tumor regression at both doses, with nominal effect on mean body weights over the course of the study period (Figure 7). Evaluation of PD in tumor samples on day 7 demonstrated robust H3K27 methyl mark reduction for EPZ011989 at the 250 and 500 mg/kg dose over the 12 h time-course (Figure 8). Notably, the exposure for EPZ011989 at 3 h postdose is an order of magnitude higher in this experiment, using the DTAL salt, than for the corresponding dose in the PK/PD study (Figure 9). As a result, at a dose of 250 mg/kg, EPZ011989 remains over the predicted efficacious plasma levels for a minimum of 6 h, though not for the full 12 h time interval. Examination of the data in Figure 8 reveals that, even though plasma exposure does not remain over the LCC, tumor methyl mark levels do not rebound during the dosing interval at 500 nor 250 mg/kg. This suggests that the observed efficacious exposure of EPZ011989 required for tumor growth inhibition is even lower than the level predicted by the LCC (lowest cytotoxic concentration) and that persistent methyl mark inhibition likely accounts for the resultant antitumor activity at lower exposure. Reference: ACS Med Chem Lett. 2015 May 14; 6(5): 491–495. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4434464/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 55.0 | 90.79 | |
| DMF | 10.0 | 16.51 | |
| Ethanol | 60.0 | 99.04 | |
| Ethanol:PBS (pH 7.2) (1:1) | 0.5 | 0.83 |
The following data is based on the product molecular weight 605.82 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. Mao S, Chaerkady R, Yu W, D'Angelo G, Garcia A, Chen H, Barrett AM, Phipps S, Fleming R, Hess S, Koopmann JO, Dimasi N, Wilson S, Pugh K, Cook K, Masterson LA, Gao C, Wu H, Herbst R, Howard PW, Tice DA, Cobbold M, Harper J. Resistance to Pyrrolobenzodiazepine Dimers Is Associated with SLFN11 Downregulation and Can Be Reversed through Inhibition of ATR. Mol Cancer Ther. 2021 Mar;20(3):541-552. doi: 10.1158/1535-7163.MCT-20-0351. PMID: 33653945. 2. Campbell JE, Kuntz KW, Knutson SK, Warholic NM, Keilhack H, Wigle TJ, Raimondi A, Klaus CR, Rioux N, Yokoi A, Kawano S, Minoshima Y, Choi HW, Porter Scott M, Waters NJ, Smith JJ, Chesworth R, Moyer MP, Copeland RA. EPZ011989, A Potent, Orally-Available EZH2 Inhibitor with Robust in Vivo Activity. ACS Med Chem Lett. 2015 Mar 4;6(5):491-5. doi: 10.1021/acsmedchemlett.5b00037. PMID: 26005520; PMCID: PMC4434464. |
| In vitro protocol: | Mao S, Chaerkady R, Yu W, D'Angelo G, Garcia A, Chen H, Barrett AM, Phipps S, Fleming R, Hess S, Koopmann JO, Dimasi N, Wilson S, Pugh K, Cook K, Masterson LA, Gao C, Wu H, Herbst R, Howard PW, Tice DA, Cobbold M, Harper J. Resistance to Pyrrolobenzodiazepine Dimers Is Associated with SLFN11 Downregulation and Can Be Reversed through Inhibition of ATR. Mol Cancer Ther. 2021 Mar;20(3):541-552. doi: 10.1158/1535-7163.MCT-20-0351. PMID: 33653945. |
| In vivo protocol: | Campbell JE, Kuntz KW, Knutson SK, Warholic NM, Keilhack H, Wigle TJ, Raimondi A, Klaus CR, Rioux N, Yokoi A, Kawano S, Minoshima Y, Choi HW, Porter Scott M, Waters NJ, Smith JJ, Chesworth R, Moyer MP, Copeland RA. EPZ011989, A Potent, Orally-Available EZH2 Inhibitor with Robust in Vivo Activity. ACS Med Chem Lett. 2015 Mar 4;6(5):491-5. doi: 10.1021/acsmedchemlett.5b00037. PMID: 26005520; PMCID: PMC4434464. |
1: Campbell JE, Kuntz KW, Knutson SK, Warholic NM, Keilhack H, Wigle TJ, Raimondi A, Klaus CR, Rioux N, Yokoi A, Kawano S, Minoshima Y, Choi HW, Porter Scott M, Waters NJ, Smith JJ, Chesworth R, Moyer MP, Copeland RA. EPZ011989, A Potent, Orally-Available EZH2 Inhibitor with Robust in Vivo Activity. ACS Med Chem Lett. 2015 Mar 4;6(5):491-5. doi: 10.1021/acsmedchemlett.5b00037. eCollection 2015 May 14. PubMed PMID: 26005520; PubMed Central PMCID: PMC4434464.
