Cell lines

SMARCB1-deficient MRT cells

Preparation method

Limited solubility. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reaction Conditions

4-7 days

Applications

EPZ-6438 induces a reduction of global H3K27Me3 level in a concentration-dependent manner. In addition, EPZ-6438 leads to a substantial antiproliferative effects as IC50 values within nanomolar range. Treatment of EPZ-6438 results in expression of CD133, DOCK4, and PTPRK and up-regulates CDKN1A and CDKN2A and BIN1in a time-dependent manner.

Animal models

SCID mice bearing EZH2-mutant lymphoma xenografts.

Dosage form

3 times daily every 8 hours, 2 times a day every 12 hours, or once a day schedules for either 7 or 28 days by oral gavage.

Applications

EPZ-6438 dose-dependently causes a reduction of tumor H3K27Me3 levels (EC50 =23 nmol/L). EPZ-6438 also shows a remarkable antitumor effects in a dose dependent manner with 2 cycles of 7-day on/7-day off and 21-day on/7-day off schedules. All EPZ-6438 dose groups except the lowest one leads to complete tumor regressions.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

• Nat Commun 11.1 (2020): 1-17.
• Cancer Res (2021).PMID: 34210752

EPZ-6438 is a potent and bio-available inhibitor of EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2) catalyzing the methylation of lysine 27 of histone H3 (H3K27), that inhibits the activity of human PRC2-containing wild-type EZH2 with a value of inhibition constantK_iof 2.5 nM. EPZ-6438 competitively binds to the S-adenosylmethionine (SAM) binding site of EZH2 and also non-competitively binds to the binding sites of peptide or nucleosome substrate. EPZ-6438 selectively inhibits EZH2 with selectivity 35-fold greater than EZH1. Study results have suggested that EPZ-6438 exhibits dramatic and permanent anti-tumor activity in MRT models through synergistic effects of EPZ-6438-mediated EZH2 inhibition on several cancer pathways.

Reference

[1].Sarah K. Knutson1, Natalie M. Warholic, Tim J. Wigle, Christine R. Klaus, Christina J. Allain, Alejandra Raimondi, Margaret Porter Scott, Richard Chesworth, Mikel P. Moyer, Robert A. Copeland, Victoria M. Richon, Roy M. Pollock, Kevin W. Kuntz, and Heike Keilhack. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. PNAS 2013; 110(19): 7922-7927