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

Area of Science:

• Oncology
• Pharmacology
• Immunology

Background:

• Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited therapeutic options.
• Multitarget drug strategies offer a promising avenue for TNBC treatment.
• Targeting both ROCK and HDAC pathways presents a novel approach.

Purpose of the Study:

• To identify and characterize novel dual ROCK/HDAC inhibitors for TNBC.
• To evaluate the efficacy and safety of compound 10h in preclinical models.
• To investigate the immunomodulatory effects of compound 10h.

Main Methods:

• Combinatorial chemistry and virtual screening to discover benzothiophene compounds.
• In vitro enzyme inhibition assays for ROCK1/2 and HDAC1/2/3/6/8.
• Antiproliferative assays against breast cancer cell lines.
• In vivo efficacy studies in an orthotopic mouse model.
• Immunogenic cell death (ICD) and immune cell activation assays.

Main Results:

• Compound 10h potently inhibited ROCK1/2 and HDAC1/2/3/6/8.
• 10h demonstrated significant antiproliferative activity against breast cancer cells.
• In vivo, 10h suppressed tumor growth without apparent toxicity.
• 10h induced ICD, promoted dendritic cell maturation, and activated T cells.

Conclusions:

• Compound 10h is a novel dual-target ROCK/HDAC inhibitor with potent anticancer activity.
• 10h exhibits promising therapeutic potential for TNBC by combining direct tumor cell killing with immune system activation.
• The immunomodulatory effects of 10h suggest a new strategy for enhancing antitumor immunity in TNBC treatment.