Discovery of Potent and Selective G9a Degraders for the Treatment of Pancreatic Cancer,Journal of Medicinal Chemistry

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Discovery of Potent and Selective G9a Degraders for the Treatment of Pancreatic Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-07-23 , DOI: 10.1021/acs.jmedchem.4c01192
Yunkai Shi _{1,

2,

3} , Qianqian Shen ₄ , Ruikai Long _{2,

3} , Yiwen Mao _{2,

3} , Shuaihang Tong _{2,

3} , Yaxi Yang _{1,

2,

3,

5} , Jing Gao _{3,

6} , Hu Zhou _{3,

6} , Yi Chen _{3,

4,

5} , Bing Zhou _{1,

2,

3,

5}

Affiliation

G9a, which was initially identified as a histone H3 Lys9 (H3K9) methyltransferase, is potentially an attractive therapeutic target for human cancers. Despite its importance, there is no available selective G9a chemical probe because its homologous protein GLP shares approximately 80% of its sequence with G9a. The development of G9a chemical probes with high selectivity for G9a over GLP is a big challenge but is extremely valuable for understanding G9a-related biology. Herein, we developed a first-in-class selective G9a degrader G9D-4, which induced a dose- and time-dependent G9a degradation without degradation of GLP. G9D-4 exhibited effective antiproliferative activities in a panel of pancreatic cancer cell lines and was able to sensitize KRAS^G12D mutant pancreatic cancer cells to KRAS^G12D inhibitor MRTX1133. These data clearly demonstrated the practicality and importance of a selective G9a degrader as a preliminary chemical probe suitable for understanding G9a-related biology and a promising strategy for the treatment of pancreatic cancer.

中文翻译：

发现用于治疗胰腺癌的有效和选择性 G9a 降解剂

G9a 最初被鉴定为组蛋白 H3 Lys9 (H3K9) 甲基转移酶，可能是人类癌症的一个有吸引力的治疗靶点。尽管它很重要，但目前还没有可用的选择性 G9a 化学探针，因为其同源蛋白 GLP 与 G9a 共享大约 80% 的序列。开发对 G9a 比 GLP 具有高选择性的 G9a 化学探针是一个巨大的挑战，但对于理解 G9a 相关的生物学非常有价值。在此，我们开发了一种一流的选择性 G9a 降解剂G9D-4 ，它诱导剂量和时间依赖性的 G9a 降解而不降解 GLP。 G9D-4在一组胰腺癌细胞系中表现出有效的抗增殖活性，并且能够使 KRAS ^G12D突变型胰腺癌细胞对 KRAS ^G12D抑制剂 MRTX1133 敏感。这些数据清楚地证明了选择性 G9a 降解剂作为适合了解 G9a 相关生物学的初步化学探针和治疗胰腺癌的有前景策略的实用性和重要性。

更新日期：2024-07-23

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