EPZ004777 hydrochloride, the hydrochloride salt of EPZ-004777, is a novel and potent DOT1L inhibitor with an IC50 value of 400 pM. DOT1L is a protein methyltransferase catalyzing the methylation of lysine 4 of histone H3 (H3K4).
Physicochemical Properties
| Molecular Formula | C₂₈H₄₂CLN₇O₄ |
| Molecular Weight | 576.13 |
| Exact Mass | 575.299 |
| CAS # | 1380316-03-9 |
| Related CAS # | EPZ004777;1338466-77-5 |
| PubChem CID | 67811385 |
| Appearance | Light yellow to yellow solid powder |
| LogP | 4.513 |
| Hydrogen Bond Donor Count | 6 |
| Hydrogen Bond Acceptor Count | 8 |
| Rotatable Bond Count | 10 |
| Heavy Atom Count | 40 |
| Complexity | 788 |
| Defined Atom Stereocenter Count | 4 |
| SMILES | CC(C)N(CCCNC(=O)NC1=CC=C(C=C1)C(C)(C)C)C[C@@H]2[C@H]([C@H]([C@@H](O2)N3C=CC4=C(N=CN=C43)N)O)O.Cl |
| InChi Key | NPEPLDAFAVXSBD-XRJUUMFPSA-N |
| InChi Code | InChI=1S/C28H41N7O4.ClH/c1-17(2)34(13-6-12-30-27(38)33-19-9-7-18(8-10-19)28(3,4)5)15-21-22(36)23(37)26(39-21)35-14-11-20-24(29)31-16-32-25(20)35;/h7-11,14,16-17,21-23,26,36-37H,6,12-13,15H2,1-5H3,(H2,29,31,32)(H2,30,33,38);1H/t21-,22-,23-,26-;/m1./s1 |
| Chemical Name | 1-[3-[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxyoxolan-2-yl]methyl-propan-2-ylamino]propyl]-3-(4-tert-butylphenyl)urea;hydrochloride |
| Synonyms | EPZ 004777 HCl EPZ-004777 EPZ004777 |
| 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 (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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
| ln Vitro | EPZ004777 hydrochloride, with an IC50 of 400±100 pM, has a strong concentration-suspension inhibitory action on DOT1L enzyme activity. On DOT1L, solutions of hydrochloride EPZ004777 suspend more HMTs (PRMT5, 521±137 nM; other, >50 μM). Prolonged HCl treatment with EPZ004777 has a substantial potential impact on MLL-rearranged cell lines. EPZ004777 hydrochloride markedly decreased the amount of viable MV4-11 and MOLM-13 cells, however it took some time for Jurkat cells to start growing. While Part One MV4-11 cells continued to divide when exposed to EPZ004777 hydrochloride, their population size did not alter over time, according to long-term growth curve tracking. At doses of 3 μM or above, EPZ004777 hydrochloride significantly inhibits MLL-AF9. Results MLL-AF10 and CALM-AF10 transformed cells' bone marrow stroma are inhibited by the EPZ004777 hydrochloride cycle [2]. | ||
| ln Vivo | The hydrochloride of EPZ004777 was well tolerated, and no appreciable toxicity was seen. Following 14 days of nonstop exposure to EPZ004777 hydrochloride, a complete blood count study revealed a substantial rise in total leukocytes as a result of an increase in neutrophils, monocytes, and lymphocytes. The hydrochloride dosage of EPZ004777 (50, 100, or 150 mg/mL) was well tolerated, and no appreciable weight loss was seen [1]. | ||
| Animal Protocol |
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| References |
[1]. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell. 2011 Jul 12;20(1):53-65. [2]. Abrogation of MLL-AF10 and CALM-AF10-mediated transformation through genetic inactivation or pharmacological inhibition of the H3K79 methyltransferase Dot1l. Leukemia. 2013 Apr;27(4):813-22. [3]. Leukemic transformation by the MLL-AF6 fusion oncogene requires the H3K79 methyltransferase Dot1l.Blood. 2013 Mar 28;121(13):2533-41. |
Solubility Data
| Solubility (In Vitro) |
H2O : ~100 mg/mL (~173.57 mM) DMSO : ~100 mg/mL (~173.57 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: 100 mg/mL (173.57 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7357 mL | 8.6786 mL | 17.3572 mL | |
| 5 mM | 0.3471 mL | 1.7357 mL | 3.4714 mL | |
| 10 mM | 0.1736 mL | 0.8679 mL | 1.7357 mL |