Six Years (2012–2018) of Researches on Catalytic EZH2 Inhibitors: The Boom of the 2‐Pyridone Compounds

Abstract

Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the Polycomb repressive complex 2 (PRC2), catalyzes the methylation of lysine 27 of histone H3 (H3K27) up to its trimethylated form (H3K27me), inducing by this way block of transcription and gene silencing. High levels of H3K27me3 have been found in both hematological malignancies and solid cancers, due to EZH2 overexpression and/or EZH2 mutation. From 2012, a number of highly potent and selective catalytic inhibitors of EZH2 have been reported, almost all bearing a 2‐pyridone group in their structure. Typically, 2‐pyridone inhibitors are selective for EZH2 over other methyltransferases, and some of them are specific for EZH2 over EZH1, others behave as dual EZH2/EZH1 inhibitors. The 2‐pyridone moiety was crucial for the enzyme inhibition, as revealed later by crystallographic studies because it occupies partially the site for the co‐substrate SAM (or the by‐product, SAH) in the binding pocket of the enzyme, accounting for the SAM‐competitive mechanism of action displayed by all the 2‐pyridone inhibitors. The 2‐pyridone warhead is linked to a support substructure, that can be either a bicyclic heteroaromatic ring (such as indazole, see for instance EPZ005687 and UNC1999, or indole, see for instance GSK126, EI1, and the more recent CPI‐1205) or a simple monocyclic (hetero) aromatic ring (tazemetostat, MC3629, (R)‐OR‐S1/2), eventually annulated with the amide chain carrying the 2‐pyridone group (3,4‐dihydroisoquinoline‐1(2H)‐ones). Different substitutions at the support moiety influence the pharmacokinetics and pharmacodynamics of the compounds as well as their water solubility. In cancer diseases, the first reported 2‐pyridone inhibitors displayed high antiproliferative effects in vitro and in vivo in lymphomas characterized by mutant EZH2 (such as Y641N), but the most recent compounds exert their anticancer activity against tumors with wild‐type EZH2 as well. The dual EZH2/1 inhibitors have been recently reported to be more effective than EZH2 selective inhibitors in specific leukemias including leukemias cancer stem cells.

Telomere dysfunction cooperates with epigenetic alterations to impair murine embryonic stem cell fate commitment

“…Unlike normal cells, the cancer epigenome is exceptionally plastic, particularly within non-coding regions, and is particularly so upon PRC2 inhibition (Fioravanti et al, 2018;Lan et al, 2017;M. Dawson, 2017;Stricker et al, 2013;Zhou et al, 2016).…”

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

“…Differently, from DNA methylation, lysine methylation can lead to either transcriptional activation or repression, depending on the specific lysine residue modified, and on the extent of methylation (me1, me2, or me3). GSK2816126 18 , tazemetostat 19 , and CPI‐1205 20 (Table ) are selective, catalytic inhibitors of both wild type (wt) and mutant forms of the methyltransferase enhancer of zeste homolog 2 (EZH2), currently in clinical trials in patients with various lymphomas, MM, and solid tumors . Pinometostat 21 (Table ) is a picomolar inhibitor of the H3K79 methyltransferase disruptor of telomeric silencing 1‐like (DOT1L), with more than 30 000‐fold selectivity against other KMTs.…”

“…18, tazemetostat 19, and CPI-1205 20 (Table 1) are selective, catalytic inhibitors of both wild type (wt) and mutant forms of the methyltransferase enhancer of zeste homolog 2 (EZH2), currently in clinical trials in patients with various lymphomas, MM, and solid tumors. 23,24 Pinometostat 21 (Table 1) is a picomolar inhibitor of the H3K79 methyltransferase disruptor of telomeric silencing 1-like (DOT1L), with more than 30 000-fold selectivity against other KMTs. When used in rearranged-MLL (mixed-lineage-leukemia) cells and xenograft models, 21 reduced H3K79 methylation level, decreased MLL target gene expression, and induced selective leukemia cell death.…”

“…has been conducted with the aim to evaluate the PK and the safety of this combination. [22][23][24][25][26][27][28]. AML makes the affected subjects more susceptible to fungal infections, therefore posaconazole 49 resulted effective to prevent this condition.…”

H3K27me3 is dispensable for early differentiation but required to maintain differentiated cell identity

“…Consequently, there is significant interest in targeting this complex pharmaceutically. Small molecules that inhibit PRC2 methyltransferase activity have been approved for clinical trials (Fioravanti et al, 2018;Kondo, 2014;Liu et al, 2015;Lue & Amengual, 2018;Qi et al, 2012;Shi et al, 2019;Xu et al, 2015;Yamagishi & Uchimaru, 2017;Yang et al, 2019). It remains, however, unclear how far this activity can be manipulated before risking adverse effects from having too little of the modification present.…”