Development of a First-in-Class DNMT1/HDAC Inhibitor with Improved Therapeutic Potential and Potentiated Antitumor Immunity,Journal of Medicinal Chemistry

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Development of a First-in-Class DNMT1/HDAC Inhibitor with Improved Therapeutic Potential and Potentiated Antitumor Immunity
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-12 , DOI: 10.1021/acs.jmedchem.4c01310
Yingjie Chang ₁ , Huahui Guo _{2,

3} , Xue Li ₁ , Liangyi Zong _{2,

3} , Jiale Wei ₄ , Zhihai Li ₄ , Cheng Luo _{4,

5} , Xinying Yang ₁ , Hao Fang ₁ , Xiangqian Kong _{2,

3} , Xuben Hou ₁

Affiliation

Epigenetic therapies have emerged as a key paradigm for treating malignancies. In this study, a series of DNMT1/HDAC dual inhibitors were obtained by fusing the key pharmacophores from DNMT1 inhibitors (DNMT1i) and HDAC inhibitors (HDACi). Among them, compound (R)-23a demonstrated significant DNMT1 and HDAC inhibition both in vitro and in cells and largely phenocopied the synergistic effects of combined DNMT1i and HDACi in reactivating epigenetically silenced tumor suppressor genes (TSGs). This translated into a profound tumor growth inhibition (TGI = 98%) of (R)-23a in an MV-4-11 xenograft model, while displaying improved tolerability compared with single agent combination. Moreover, in a syngeneic MC38 mouse colorectal tumor model, (R)-23a outperformed the combinatory treatment in reshaping the tumor immune microenvironment and inducing tumor regression. Collectively, the novel DNMT1/HDAC dual inhibitor (R)-23a effectively reverses the cancer-specific epigenetic abnormalities and holds great potential for further development into cancer therapeutic agents.

中文翻译：

开发具有更高治疗潜力和增强抗肿瘤免疫力的同类首创 DNMT1/HDAC 抑制剂

表观遗传学疗法已成为治疗恶性肿瘤的关键范式。在本研究中，通过融合 DNMT1 抑制剂（DNMT1i）和 HDAC 抑制剂（HDACi）的关键药效团，获得了一系列 DNMT1/HDAC 双重抑制剂。其中，化合物（R）-23a 在体外和细胞中均表现出显著的 DNMT1 和 HDAC 抑制作用，并且在很大程度上表型复制了 DNMT1i 和 HDACi 联合在重新激活表观遗传沉默的肿瘤抑制基因（TSG）中的协同作用。这转化为 MV-4-11 异种移植模型中（R）-23a 的深刻肿瘤生长抑制（TGI = 98%），同时与单一药物组合相比显示出更高的耐受性。此外，在同基因 MC38 小鼠结直肠肿瘤模型中，（R）-23a 在重塑肿瘤免疫微环境和诱导肿瘤消退方面优于联合治疗。总的来说，新型 DNMT1/HDAC 双重抑制剂（R）-23a 有效逆转癌症特异性表观遗传异常，并具有进一步开发为癌症治疗剂的巨大潜力。

更新日期：2024-09-12

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