Design, synthesis and biological evaluation of WEE1 degraders via HSP90-mediated targeting chimeras for target therapy of acute myeloid leukemia.

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Tác giả: Tingting He, Jia Li, Xiaomei Li, Minmin Liu, Wei Lu, Jingkun Ma, Jialuo Mao, Huijing Wang, Xiaoxuan Yu, Xiangying Zhai, Yubo Zhou, Shulei Zhu

Ngôn ngữ: eng

Ký hiệu phân loại:

Thông tin xuất bản: France : European journal of medicinal chemistry , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 726740

Targeted protein degradation (TPD) technology is a promising strategy for drug development, while the on-target off-tumor risks of current TPD technologies were intractable. Herein, a series of (HSP90)-mediated targeting chimeras (HEMTACs) based WEE1-target degraders were designed to enhance the efficiency and decrease off-tumor risks. Among them, 8b and 9c could effectively degrade cellular WEE1 protein and exhibited superior anti-proliferative activity in MV-4-11 cells by inducing cell cycle arrest in G2/M phase. Meanwhile, 8b and 9c exhibited high selectivity to primary AML cells over normal cells. Furthermore, 3 mg/kg of 9c demonstrated superior anti-cancer activity than 5 mg/kg AZD1775 in an AML PDX model. And most importantly, 9c exhibited lower hematotoxicity than equimolar AZD1775 in mice safety evaluation, suggesting that 9c is a promising degrader for AML target therapy, comfirming that HSP90-based HEMTACs is a valid strategy to reduce off-tumor risks.
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