2. Academic Validation
  3. Discovery of the First-in-Class Dual-Target ROCK/HDAC Inhibitor with Potent Antitumor Efficacy in Vivo That Trigger Antitumor Immunity

Discovery of the First-in-Class Dual-Target ROCK/HDAC Inhibitor with Potent Antitumor Efficacy in Vivo That Trigger Antitumor Immunity

  • J Med Chem. 2024 Nov 10. doi: 10.1021/acs.jmedchem.4c02183.
Churu Mao 1,  Jiebin Fang 2,  Shijie Zou 1,  Yun Huang 1,  Xiaoming Chen 1,  Xia Ding 1,  Zhangyun Fang 1,  Ningjing Zhang 1,  Yijie Lou 3,  Zhe Chen 3,  Wanjing Ding 1 2,  Zhongjun Ma 1 2
Affiliations

Affiliations

  • 1 Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan 316021, China.
  • 2 Hainan Institute of Zhejiang University, Sanya 572025, China.
  • 3 Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, China.
PMID: 39523548 DOI: 10.1021/acs.jmedchem.4c02183
Abstract

Triple-negative breast Cancer (TNBC) represents a highly aggressive and heterogeneous malignancy. Currently, multitarget drug approaches present a promising therapeutic approach for TNBC. Utilizing a combinatorial chemistry strategy to construct a virtual screening database, dual ROCK/HDAC-targeting benzothiophene compounds were identified. Notably, compound 10h effectively inhibits ROCK1/2 and HDAC1/2/3/6/8 while demonstrating potent antiproliferative activity against breast Cancer cells. In an orthotopic mouse model of breast Cancer, 10h significantly suppressed tumor growth without apparent toxicity. Importantly, 10h induced immunogenic cell death (ICD), promoted dendritic cells (DCs) maturation, and activated T cells, thereby initiating antitumor immunity. In conclusion, compound 10h is a novel dual-target ROCK/HDAC Inhibitor that represents a promising treatment strategy for TNBC.

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