Discovery of a potential hematologic malignancies therapy: Selective and potent HDAC7 PROTAC degrader targeting non-enzymatic function.

Yuheng JIN; Xuxin QI; Xiaoli YU; Xirui CHENG; Boya CHEN; Mingfei WU; Jingyu ZHANG; Hao YIN; Yang LU; Yihui ZHOU; Ao PANG; Yushen LIN; Li JIANG; Qiuqiu SHI; Shuangshuang GENG; Yubo ZHOU; Xiaojun YAO; Linjie LI; Haiting DUAN; Jinxin CHE; Ji CAO; Qiaojun HE; Xiaowu DONG

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Discovery of a potential hematologic malignancies therapy: Selective and potent HDAC7 PROTAC degrader targeting non-enzymatic function.

Author: Yuheng JIN ¹ ; Xuxin QI ² ; Xiaoli YU ¹ ; Xirui CHENG ² ; Boya CHEN ² ; Mingfei WU ¹ ; Jingyu ZHANG ¹ ; Hao YIN ² ; Yang LU ¹ ; Yihui ZHOU ² ; Ao PANG ¹ ; Yushen LIN ² ; Li JIANG ² ; Qiuqiu SHI ¹ ; Shuangshuang GENG ¹ ; Yubo ZHOU ³ ; Xiaojun YAO ⁴ ; Linjie LI ¹ ; Haiting DUAN ¹ ; Jinxin CHE ¹ ; Ji CAO ² ; Qiaojun HE ² ; Xiaowu DONG ¹
Author Information

1. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
2. Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences and Cancer Center, Zhejiang University, Hangzhou 310058, China.
3. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Guangdong 528400, China.
4. Centre for Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao 999078, China.
Publication Type:Journal Article
Keywords: HDAC7; Hematologic malignancies; Non-enzymatic function; PROTAC; Selectivity
From: Acta Pharmaceutica Sinica B 2025;15(3):1659-1679
CountryChina
Language:English
Abstract: HDAC7, a member of class IIa HDACs, plays a pivotal regulatory role in tumor, immune, fibrosis, and angiogenesis, rendering it a potential therapeutic target. Nevertheless, due to the high similarity in the enzyme active sites of class IIa HDACs, inhibitors encounter challenges in discerning differences among them. Furthermore, the substitution of key residue in the active pocket of class IIa HDACs renders them pseudo-enzymes, leading to a limited impact of enzymatic inhibitors on their function. In this study, proteolysis targeting chimera (PROTAC) technology was employed to develop HDAC7 drugs. We developed an exceedingly selective HDAC7 PROTAC degrader B14 which showcased superior inhibitory effects on cell proliferation compared to TMP269 in various diffuse large B cell lymphoma (DLBCL) and acute myeloid leukemia (AML) cells. Subsequent investigations unveiled that B14 disrupts BCL6 forming a transcriptional inhibition complex by degrading HDAC7, thereby exerting proliferative inhibition in DLBCL. Our study broadened the understanding of the non-enzymatic functions of HDAC7 and underscored the importance of HDAC7 in the treatment of hematologic malignancies, particularly in DLBCL and AML.