Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 16, Pages 11774-11797Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00226
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Funding
- MIUR [AIRC2016 IG-19162]
- Sapienza Ateneo Project [PON R&I 2014-2020-AIM1873131-2]
- [RG120172B8E53D03]
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Recent research has shown that disrupting the multimeric integrity of the PRC2 complex to cripple its function is a promising approach in cancer treatment. Developing EZH2-EED protein-protein interaction and EED inhibitors as indirect modulators of PRC2-dependent methyltransferase activity has gained significant interest in the scientific community.
Epigenetics is nowadays a well-accepted area of research. In the last years, tremendous progress was made regarding molecules targeting EZH2, directly or indirectly. Recently tazemetostat hit the market after FDA-approval for the treatment of lymphoma. However, the impairment of EZH2 activity by orthosteric intervention has proven to be effective only in a limited subset of cancers. Considering the multiproteic nature of the PRC2 complex and the marked dependence of EZH2 functions on the other core subunits such as EED, in recent years, a new targeting approach ascended to prominence. The possibility to cripple the function of the PRC2 complex by interfering with its multimeric integrity fueled the interest in developing EZH2-EED protein-protein interaction and EED inhibitors as indirect modulators of PRC2-dependent methyltransferase activity. In this Perspective, we aim to summarize the latest findings regarding the development and the biological activity of these emerging classes of PRC2 modulators from a medicinal chemist's viewpoint.
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