Polycomp group (PcG) proteins are members of highly conserved multiprotein complexes, recognized as gene transcriptional repressors during development and shown to play a role in various physiological and pathological processes. PcG proteins consist of two Polycomb repressive complexes (PRCs) with different enzymatic activities: Polycomb repressive complexes 1 (PRC1), a ubiquitin ligase, and Polycomb repressive complexes 2 (PRC2), a histone methyltransferase. Traditionally, PRCs have been described to be associated with transcriptional repression of homeotic genes, as well as gene transcription activating effects. Particularly in cancer, PRCs have been found to misregulate gene expression, not only depending on the function of the whole PRCs, but also through their separate subunits. In this review, we focused especially on the recent findings in the transcriptional regulation of PRCs, the oncogenic and tumor-suppressive roles of PcG proteins, and the research progress of inhibitors targeting PRCs.

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DCN1, a co-E3 ligase, interacts with UBC12 and activates cullin–RING ligases (CRLs) by catalyzing cullin neddylation. Although DCN1 has been recognized as an important therapeutic target for human diseases, its role in the cardiovascular area remains unknown. Here, we first found that DCN1 was upregulated in isolated cardiac fibroblasts (CFs) treated by angiotensin (Ang) II and in mouse hearts after pressure overload. Then, structure-based optimizations for DCN1-UBC12 inhibitors were performed based on our previous work, yielding compound DN-2. DN-2 specifically targeted DCN1 at molecular and cellular levels as shown by molecular modeling studies, HTRF, cellular thermal shift and co-immunoprecipitation assays. Importantly, DN-2 effectively reversed Ang II-induced cardiac fibroblast activation, which was associated with the inhibition of cullin 3 neddylation. Our findings indicate a potentially unrecognized role of DCN1 inhibition for anticardiac fibrotic effects. DN-2 may be used as a lead compound for further development.

Interrupting the embryonic ectoderm development (EED)–H3K27me3 interaction represents a promising strategy to allosterically inhibit polycomb repressive complex 2 (PRC2) for cancer therapy. In this work, we report the structure-based design of new triazolopyrimidine-based EED inhibitors, which structurally feature the electron-rich indole ring at the C8 position. Particularly, ZJH-16 directly binds to EED (HTRF IC50 = 2.72 nM, BLI K D = 4.4 nM) and potently inhibits the growth of KARPAS422 and Pfeiffer cells. In both cells, ZJH-16 is selectively engaged with EED and reduces H3K27 trimethylation levels. ZJH-16 inhibits the gene silencing function of PRC2 in KARPAS422 cells. ZJH-16 possesses favorable pharmacokinetic (PK) profiles with an excellent oral bioavailability (F = 94.7%). More importantly, ZJH-16 shows robust tumor regression in the KARPAS422 xenograft model after oral administration with the tumor growth inhibition reaching nearly 100%. The robust antitumor efficacy and favorable PK profiles of ZJH-16 warrant further advanced preclinical development for lymphoma treatment.

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