For research use only. Not for therapeutic Use.
<p style=/line-height:25px/>EPZ-5676 is a potent and selective aminonucleoside inhibitor of DOT1L histone methyltransferase with Ki of 80 pM; demonstrating >37,000-fold selectivity against all other PMTs tested, inhibits H3K79 methylation in tumor.<br>IC50 Value: 80 pM (Ki value) [1]<br>Target:<br>in vitro: The compound has a Ki value of 80 pM, and demonstrates 37,000-fold selectivity over all other methyltransferases tested. In cellular studies, EPZ-5676inhibited H3K79 methylation and MLL-fusion target gene expression and demonstrated potent cell killing that was selective for acute leukemia lines bearing MLL translocations [1].<br>in vivo: Continuous intravenous (IV) infusion of EPZ-5676 in a rat xenograft model of MLL-rearranged leukemia caused complete tumor regressions that were sustained well beyond the compound infusion period with no significant weight loss or signs of toxicity [1].<br>Clinical trial: A First-in-Human, Phase I and Expanded Cohort Study of EPZ-5676 in Advanced Hematological Malignancies, Including Acute Leukemia With Rearrangement of the MLL Gene. Phase 1<br></p>
| Catalog Number | I001465 |
| CAS Number | 1380288-87-8 |
| Synonyms | (2R,3S,4S,5R)-2-(6-aminopurin-9-yl)-5-[[[3-[2-(6-tert-butyl-1H-benzimidazol-2-yl)ethyl]cyclobutyl]-propan-2-ylamino]methyl]oxolane-3,4-diol |
| Molecular Formula | C₃₀H₄₂N₈O₃ |
| Purity | ≥95% |
| Target | Histone Methyltransferase |
| Solubility | DMSO: ≥ 47.8 mg/mL |
| Storage | 3 years -20C powder |
| IC50 | 80 pM (Ki value) [1] |
| InChI | InChI=1S/C30H42N8O3/c1-16(2)37(13-22-25(39)26(40)29(41-22)38-15-34-24-27(31)32-14-33-28(24)38)19-10-17(11-19)6-9-23-35-20-8-7-18(30(3,4)5)12-21(20)36-23/h7-8,12,14-17,19,22,25-26,29,39-40H,6,9-11,13H2,1-5H3,(H,35,36)(H2,31,32,33)/t17-,19+,22-,25-,26-,29-/ |
| InChIKey | LXFOLMYKSYSZQS-LURJZOHASA-N |
| SMILES | CC(C)(C)C1=CC2=C(NC(CC[[email protected]]3C[[email protected]@H](N(C[[email protected]@H]4[[email protected]@H](O)[[email protected]@H](O)[[email protected]](N5C(N=CN=C6C6N)=C6N=C5)O4)C(C)C)C3)=N2)C=C1 |
| Reference | </br>1:Mechanisms of Pinometostat (EPZ-5676) Treatment Emergent Resistance in MLL Rearranged Leukemia. Campbell CT, Haladyna JN, Drubin DA, Thomson TM, Maria MJ, Yamauchi T, Waters NJ, Olhava EJ, Pollock RM, Smith JJ, Copeland RA, Blakemore SJ, Bernt KM, Daigle SR.Mol Cancer Ther. 2017 Apr 20. pii: molcanther.0693.2016. doi: 10.1158/1535-7163.MCT-16-0693. [Epub ahead of print] PMID: 28428443 </br>2:Preclinical Pharmacokinetics and Pharmacodynamics of Pinometostat (EPZ-5676), a First-in-Class, Small Molecule S-Adenosyl Methionine Competitive Inhibitor of DOT1L. Waters NJ.Eur J Drug Metab Pharmacokinet. 2017 Feb 22. doi: 10.1007/s13318-017-0404-3. [Epub ahead of print] PMID: 28229434 </br>3:[Mechanism of A New DOT1L Inhibitor EPZ-5676 and Its Research Progress -Review]. Li LH, Wang J, Ke XY.Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2016 Dec;24(6):1909-1912. doi: 10.7534/j.issn.1009-2137.2016.06.055. Chinese. PMID: 28024519 </br>4:Metabolism and disposition of the DOT1L inhibitor, pinometostat (EPZ-5676), in rat, dog and human. Waters NJ, Smith SA, Olhava EJ, Duncan KW, Burton RD, O/’Neill J, Rodrigue ME, Pollock RM, Moyer MP, Chesworth R.Cancer Chemother Pharmacol. 2016 Jan;77(1):43-62. doi: 10.1007/s00280-015-2929-y. Epub 2015 Dec 8. PMID: 26645404 </br>5:Exploring drug delivery for the DOT1L inhibitor pinometostat (EPZ-5676): Subcutaneous administration as an alternative to continuous IV infusion, in the pursuit of an epigenetic target. Waters NJ, Daigle SR, Rehlaender BN, Basavapathruni A, Campbell CT, Jensen TB, Truitt BF, Olhava EJ, Pollock RM, Stickland KA, Dovletoglou A.J Control Release. 2015 Dec 28;220(Pt B):758-65. doi: 10.1016/j.jconrel.2015.09.023. Epub 2015 Sep 15. PMID: 26385168 </br>6:DOT1L inhibitor EPZ-5676 displays synergistic antiproliferative activity in combination with standard of care drugs and hypomethylating agents in MLL-rearranged leukemia cells. Klaus CR, Iwanowicz D, Johnston D, Campbell CA, Smith JJ, Moyer MP, Copeland RA, Olhava EJ, Scott MP, Pollock RM, Daigle SR, Raimondi A.J Pharmacol Exp Ther. 2014 Sep;350(3):646-56. doi: 10.1124/jpet.114.214577. Epub 2014 Jul 3. PMID: 24993360 Free Article</br>7:Nonclinical pharmacokinetics and metabolism of EPZ-5676, a novel DOT1L histone methyltransferase inhibitor. Basavapathruni A, Olhava EJ, Daigle SR, Therkelsen CA, Jin L, Boriack-Sjodin PA, Allain CJ, Klaus CR, Raimondi A, Scott MP, Dovletoglou A, Richon VM, Pollock RM, Copeland RA, Moyer MP, Chesworth R, Pearson PG, Waters NJ.Biopharm Drug Dispos. 2014 May;35(4):237-52. doi: 10.1002/bdd.1889. Epub 2014 Feb 14. PMID: 24415392 |
