EPZ-5676 - CAS 1380288-87-8
Catalog number: 1380288-87-8
Category: Inhibitor
Not Intended for Therapeutic Use. For research use only.
COA:
Inquire
Targets:
HMTase
Description:
EPZ-5676 is a small molecule inhibitor of histone methyltransferase with potential antineoplastic activity. Upon intravenous administration, EPZ-5676 specifically blocks the activity of the histone lysine-methyltransferase DOT1L, thereby inhibiting the methylation of nucleosomal histone H3 on lysine 79 (H3K79) that is bound to the mixed lineage leukemia (MLL) fusion protein which targets genes and blocks the expression of leukemogenic genes. This eventually leads to an induction of apoptosis in the leukemic cells bearing the MLL gene translocations. DOT1L, a non-SET domain-containing histone methyltransferase, specifically methylates H3K79 and plays a key role in normal cell differentiation and in the development of leukemia with MLL gene rearrangement on chromosome 11 and promotes the expression of leukemia-causing genes.
Publictions citing BOC Sciences Products
  • >> More
Appearance:
white solid powder
Synonyms:
EPZ-5676; EPZ5676; EPZ 5676.
MSDS:
Inquire
Current Developer:
Epizyme
1.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 NJ1, Daigle SR1, Rehlaender BN2, Basavapathruni A1, Campbell CT1, Jensen TB1, Truitt BF1, Olhava EJ3, Pollock RM4, Stickland KA5, Dovletoglou A1. J Control Release. 2015 Dec 28;220(Pt B):758-65. doi: 10.1016/j.jconrel.2015.09.023. Epub 2015 Sep 15.
Protein methyltransferases are emerging as promising drug targets for therapeutic intervention in human cancers. Pinometostat (EPZ-5676) is a small molecule inhibitor of the DOT1L enzyme, a histone methyltransferase that methylates lysine 79 of histone H3. DOT1L activity is dysregulated in the pathophysiology of rearranged mixed lineage leukemia (MLL-r). Pinometostat is currently in Phase 1 clinical trials in relapsed refractory acute leukemia patients and is administered as a continuous IV infusion (CIV). The studies herein investigated alternatives to CIV administration of pinometostat to improve patient convenience. Various sustained release technologies were considered, and based on the required dose size as well as practical considerations, subcutaneous (SC) bolus administration of a solution formulation was selected for further evaluation in preclinical studies. SC administration offered improved exposure and complete bioavailability of pinometostat relative to CIV and oral administration.
2.Nonclinical pharmacokinetics and metabolism of EPZ-5676, a novel DOT1L histone methyltransferase inhibitor.
Basavapathruni A1, 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.
(2R,3R,4S,5R)-2-(6-Amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol (EPZ-5676) is a novel DOT1L histone methyltransferase inhibitor currently in clinical development for the treatment of MLL-rearranged leukemias. This report describes the preclinical pharmacokinetics and metabolism of EPZ-5676, an aminonucleoside analog with exquisite target potency and selectivity that has shown robust and durable tumor growth inhibition in preclinical models. The in vivo pharmacokinetics in mouse, rat and dog were characterized following i.v. and p.o. administration; EPZ-5676 had moderate to high clearance, low oral bioavailability with a steady-state volume of distribution 2-3 fold higher than total body water. EPZ-5676 showed biexponential kinetics following i.v. administration, giving rise to a terminal elimination half-life (t1/2 ) of 1.1, 3.7 and 13.6 h in mouse, rat and dog, respectively.
3.Metabolism and disposition of the DOT1L inhibitor, pinometostat (EPZ-5676), in rat, dog and human.
Waters NJ1, Smith SA2, Olhava EJ2, Duncan KW2, Burton RD3, O'Neill J4, Rodrigue ME5, Pollock RM2, Moyer MP2, Chesworth R2. Cancer Chemother Pharmacol. 2016 Jan;77(1):43-62. doi: 10.1007/s00280-015-2929-y. Epub 2015 Dec 8.
PURPOSE: The metabolism and disposition of the first-in-class DOT1L inhibitor, EPZ-5676 (pinometostat), was investigated in rat and dog. Metabolite profiles were compared with those from adult patients in the first-in-man phase 1 study as well as the cross-species metabolism observed in vitro.
4.DOT1L inhibitor EPZ-5676 displays synergistic antiproliferative activity in combination with standard of care drugs and hypomethylating agents in MLL-rearranged leukemia cells.
Klaus CR1, Iwanowicz D1, Johnston D1, Campbell CA1, Smith JJ1, Moyer MP1, Copeland RA1, Olhava EJ1, Scott MP1, Pollock RM1, Daigle SR1, Raimondi A2. J Pharmacol Exp Ther. 2014 Sep;350(3):646-56. doi: 10.1124/jpet.114.214577. Epub 2014 Jul 3.
EPZ-5676 [(2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol], a small-molecule inhibitor of the protein methyltransferase DOT1L, is currently under clinical investigation for acute leukemias bearing MLL-rearrangements (MLL-r). In this study, we evaluated EPZ-5676 in combination with standard of care (SOC) agents for acute leukemias as well as other chromatin-modifying drugs in cellular assays with three human acute leukemia cell lines: MOLM-13 (MLL-AF9), MV4-11 (MLL-AF4), and SKM-1 (non-MLL-r). Studies were performed to evaluate the antiproliferative effects of EPZ-5676 combinations in a cotreatment model in which the second agent was added simultaneously with EPZ-5676 at the beginning of the assay, or in a pretreatment model in which cells were incubated for several days in the presence of EPZ-5676 prior to the addition of the second agent.
Molecular Weight Calculator Molarity Calculator Solution Dilution Calculator

Related HMTase Products


C7280948
(CAS: 587850-67-7)

C7280948 is a novel PRMT1 inhibitor ( IC50=12.75 μM).

CAS 1380316-03-9 EPZ004777 hydrochloride

EPZ004777 hydrochloride
(CAS: 1380316-03-9)

EPZ004777 selectively inhibits cellular H3K79 methylation and inhibits expression of key MLL fusion target genes. Following DOT1L inhibition, EPZ004777 selectiv...

CAS 1627676-59-8 PFI-2

PFI-2
(CAS: 1627676-59-8)

PFI-2 is a potent, selective, and cell-active lysine methyltransferase SETD7 inhibitor with Ki (app) and IC50 of 0.33 nM and 2 nM, 1000-fold selectivity over ot...

CAS 935693-62-2 BIX-01294

BIX-01294
(CAS: 935693-62-2)

BIX-01294, a diazepin-quinazolinamine derivative, is a selective inhibitor of G9a histone methyl transferase (G9a HMTase) that impairs G9a HMTase and generation...

CAS 1271738-59-0 MI-3

MI-3
(CAS: 1271738-59-0)

MI-3 (Menin-MLL Inhibitor) is a potent menin-MLL interaction inhibitor with IC50 of 648 nM.

CAS 1616391-65-1 EPZ015666

EPZ015666
(CAS: 1616391-65-1)

EPZ015666 shows potent cellular activity that blocks symmetric dimethylation of SmD3 and inhibit proliferation of MCL cell lines (Z-138, Granta-519, Maver-1, Mi...

CAS 1561178-17-3 SGC 0946

SGC 0946
(CAS: 1561178-17-3)

SGC0946 is a potent and selective inhibitor of DOT1L, which potently and selectively kills cells containing an MLL translocation. SGC0946 inhibits DOT1L with an...

CAS 1374601-40-7 BRD4770

BRD4770
(CAS: 1374601-40-7)

BRD4770 is a novel histone methyltransferase inhibitor. BRD4770 reduced cellular levels of di- and trimethylated H3K9 without inducing apoptosis, induced senesc...

CAS 1238673-32-9 UNC0321

UNC0321
(CAS: 1238673-32-9)

UNC0321 is the first G9a inhibitor with picomolar potency and the most potent G9a inhibitor to date. Protein lysine methyltransferase G9a, which catalyzes methy...

CAS 1271738-62-5 MI-2

MI-2
(CAS: 1271738-62-5)

MI-2 (Menin-MLL Inhibitor) is a potent menin-MLL interaction inhibitor with IC50 of 446 nM.

HLCL-61 hydrochloride
(CAS: 1158279-20-9)

The hydrochloride salt form of HLCL-61, an effective inhibitor of PRMT5, could probably useful in the treatment of acute myeloid leukemia.

CAS 1314241-44-5 UNC 669

UNC 669
(CAS: 1314241-44-5)

(5-Bromopyridin-3-yl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone is a selective inhibitor of malignant brain tumor (MBT).

CAS 1417329-24-8 MM-102

MM-102
(CAS: 1417329-24-8)

MM-102, as a MLL1 mimetic, shows high binding affinities to WDR5 with IC50 of 2.9 nM and Ki of < 1 nM.

CAS 20324-87-2 AMI-1

AMI-1
(CAS: 20324-87-2)

AMI-1 is a potent and specific Histone Methyltransferase (HMT) inhibitor with IC50 of 3.0 μM and 8.8 μM for yeast Hmt1p and human PRMT1, respectively.

CAS 1621862-70-1 CPI-1205

CPI-1205
(CAS: 1621862-70-1)

A highly potent and selective EZH2 inhibitor (biochemical IC50=2 nM, cellular EC50=32 nM)

CAS 1320288-19-4 UNC-0631

UNC-0631
(CAS: 1320288-19-4)

CAS 1020399-49-8 CARM1-IN-1

CARM1-IN-1
(CAS: 1020399-49-8)

CARM1-IN-1 is a potent and specific CARM1(Coactivator-associated arginine methyltransferase 1) inhibitor with IC50 of 8.6 μM and shows very low activity against...

UNC0642
(CAS: 1481677-78-4)

UNC0642 is a potent, selective inhibitor of G9a/GLP with improved PK properties.

CAS 1320288-17-2 UNC0646

UNC0646
(CAS: 1320288-17-2)

UNC-0646 is a novel G9a inhibitor with excellent potency in a variety of cell lines and excellent separation of functional potency versus cell toxicity.

PFI-2 hydrochloride
(CAS: 1627607-87-7)

PFI-2 hydrochloride is a potent, cell-permeable inhibitor of SET7/9 (IC50 = 2 nM) and is approximately 1,000-fold selective over a panel of 18 other methyltrans...

Chemical Structure

CAS 1380288-87-8 EPZ-5676

Quick Inquiry

Verification code

Featured Items