Discovery of the Clinical Candidate MAK683: An EED-Directed, Allosteric, and Selective PRC2 Inhibitor for the Treatment of Advanced Malignancies

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2022-03-30 DOI:10.1021/acs.jmedchem.1c02148

Ying Huang, Martin Sendzik, Jeff Zhang, Zhenting Gao, Yongfeng Sun, Long Wang, Justin Gu, Kehao Zhao, Zhengtian Yu, Lijun Zhang, Qiong Zhang, Joachim Blanz, Zijun Chen, Valérie Dubost, Douglas Fang, Lijian Feng, Xingnian Fu, Michael Kiffe, Ling Li, Fangjun Luo, Xiao Luo, Yuan Mi, Prakash Mistry, David Pearson, Alessandro Piaia, Clemens Scheufler, Remi Terranova, Andreas Weiss, Jue Zeng, Hailong Zhang, Jiangwei Zhang, Mengxi Zhao, Michael P. Dillon, Sebastien Jeay, Wei Qi, Jonathan Moggs, Carole Pissot-Soldermann, En Li, Peter Atadja, Andreas Lingel* and Counde Oyang,

{"title":"Discovery of the Clinical Candidate MAK683: An EED-Directed, Allosteric, and Selective PRC2 Inhibitor for the Treatment of Advanced Malignancies","authors":"Ying Huang, Martin Sendzik, Jeff Zhang, Zhenting Gao, Yongfeng Sun, Long Wang, Justin Gu, Kehao Zhao, Zhengtian Yu, Lijun Zhang, Qiong Zhang, Joachim Blanz, Zijun Chen, Valérie Dubost, Douglas Fang, Lijian Feng, Xingnian Fu, Michael Kiffe, Ling Li, Fangjun Luo, Xiao Luo, Yuan Mi, Prakash Mistry, David Pearson, Alessandro Piaia, Clemens Scheufler, Remi Terranova, Andreas Weiss, Jue Zeng, Hailong Zhang, Jiangwei Zhang, Mengxi Zhao, Michael P. Dillon, Sebastien Jeay, Wei Qi, Jonathan Moggs, Carole Pissot-Soldermann, En Li, Peter Atadja, Andreas Lingel* and Counde Oyang, ","doi":"10.1021/acs.jmedchem.1c02148","DOIUrl":null,"url":null,"abstract":"<p >Polycomb Repressive Complex 2 (PRC2) plays an important role in transcriptional regulation during animal development and in cell differentiation, and alteration of PRC2 activity has been associated with cancer. On a molecular level, PRC2 catalyzes methylation of histone H3 lysine 27 (H3K27), resulting in mono-, di-, or trimethylated forms of H3K27, of which the trimethylated form H3K27me3 leads to transcriptional repression of polycomb target genes. Previously, we have shown that binding of the low-molecular-weight compound EED226 to the H3K27me3 binding pocket of the regulatory subunit EED can effectively inhibit PRC2 activity in cells and reduce tumor growth in mouse xenograft models. Here, we report the stepwise optimization of the tool compound EED226 toward the potent and selective EED inhibitor MAK683 (compound <b>22</b>) and its subsequent preclinical characterization. Based on a balanced PK/PD profile, efficacy, and mitigated risk of forming reactive metabolites, MAK683 has been selected for clinical development.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"65 7","pages":"5317–5333"},"PeriodicalIF":6.8000,"publicationDate":"2022-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"17","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c02148","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 17

Abstract

Polycomb Repressive Complex 2 (PRC2) plays an important role in transcriptional regulation during animal development and in cell differentiation, and alteration of PRC2 activity has been associated with cancer. On a molecular level, PRC2 catalyzes methylation of histone H3 lysine 27 (H3K27), resulting in mono-, di-, or trimethylated forms of H3K27, of which the trimethylated form H3K27me3 leads to transcriptional repression of polycomb target genes. Previously, we have shown that binding of the low-molecular-weight compound EED226 to the H3K27me3 binding pocket of the regulatory subunit EED can effectively inhibit PRC2 activity in cells and reduce tumor growth in mouse xenograft models. Here, we report the stepwise optimization of the tool compound EED226 toward the potent and selective EED inhibitor MAK683 (compound 22) and its subsequent preclinical characterization. Based on a balanced PK/PD profile, efficacy, and mitigated risk of forming reactive metabolites, MAK683 has been selected for clinical development.

Abstract Image

查看原文本刊更多论文

临床候选药物MAK683的发现：一种用于治疗晚期恶性肿瘤的EED导向、变构和选择性PRC2抑制剂。

多梳抑制复合物2（PRC2）在动物发育和细胞分化过程中的转录调节中起着重要作用，PRC2活性的改变与癌症有关。在分子水平上，PRC2催化组蛋白H3赖氨酸27（H3K27）的甲基化，导致H3K27的单、二或三甲基化形式，其中三甲基化的形式H3K27me3导致polycomb靶基因的转录抑制。此前，我们已经表明，在小鼠异种移植物模型中，低分子量化合物EED226与调节亚基EED的H3K27me3结合口袋的结合可以有效抑制细胞中的PRC2活性并减少肿瘤生长。在此，我们报道了工具化合物EED226对强效和选择性EED抑制剂MAK683（化合物22）的逐步优化及其随后的临床前表征。基于平衡的PK/PD特征、疗效和降低形成反应性代谢产物的风险，已选择MAK683进行临床开发。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.