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

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 <b>10h</b> 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, <b>10h</b> significantly suppressed tumor growth without apparent toxicity. Importantly, <b>10h</b> induced immunogenic cell death (ICD), promoted dendritic cells (DCs) maturation, and activated T cells, thereby initiating antitumor immunity. In conclusion, compound <b>10h</b> is a novel dual-target ROCK/HDAC inhibitor that represents a promising treatment strategy for TNBC.