Delving into the Latest Updates on DC-PRC2in-01 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms-

Target

PRC2

Action

inhibitors

Mechanism

Polycomb repressive complex 2 inhibitors(Polycomb repressive complex 2 inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

Neoplasms

Inactive Indication-

Originator Organization

Shanghai Institute of Materia Medica Chinese Academy of Sci

Active Organization

Shanghai Institute of Materia Medica Chinese Academy of Sci

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Author: Ding, Yiluan ; Jiang, Hualiang ; Zhao, Kaiyan ; Fan, Shijie ; Xu, Dandan ; Luo, Zhongyuan ; Zhao, Kehao ; Zhang, Naixia ; Chen, Kaixian ; Liu, Yanli ; Liu, Jingqiu ; Zwergel, Clemens ; Du, Daohai ; Valente, Sergio ; Stazi, Giulia ; Zhu, Kongkai ; Kong, Xiangqian ; Zhang, Yuanyuan ; Zhu, Licheng ; Li, Yuanqing ; Min, Jinrong ; Duan, Wenhu ; Luo, Cheng

Disruption of EZH2-embryonic ectoderm development (EED) protein-protein interaction (PPI) is a new promising cancer therapeutic strategy. We have previously reported the discovery of astemizole, a small-molecule inhibitor targeting the EZH2-EED PPI. Herein, we report the cocrystal structure of EED in complex with astemizole at 2.15 Å. The structure elucidates the detailed binding mode of astemizole to EED and provides a structure-guided design for the discovery of a novel EZH2-EED interaction inhibitor, DC-PRC2in-01, with an affinity K_d of 4.56 μM. DC-PRC2in-01 destabilizes the PRC2 complex, thereby leading to the degradation of PRC2 core proteins and the decrease of global H3K27me3 levels in cancer cells. The proliferation of PRC2-driven lymphomas cells is effectively inhibited, and the cell cycle is arrested in the G0/G1 phase. Together, these data demonstrate that DC-PRC2in-01 could be an effective chemical probe for investigating the PRC2-related physiology and pathology and providing a promising chemical scaffold for further development.

100 Deals associated with DC-PRC2in-01

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