Design, Synthesis, and Biological Evaluation of Novel PAK1/HDAC10 Dual Inhibitors That Activate Antitumor Immunity for Triple-Negative Breast Cancer Treatment.

Triple-negative breast cancer (TNBC) remains a clinical challenge due to the lack of druggable targets, an immunosuppressive tumor microenvironment (TIME), and the limited efficacy of immune checkpoint inhibitors (ICIs). Herein, we report the first rational design, synthesis, and evaluation of dual PAK1/HDAC10 inhibitors to concurrently suppress oncogenic signaling and influence the TIME. Optimization yielded YDH-704, which displays nanomolar potency against PAK1 and HDAC10, excellent selectivity for HDAC10, and negligible off-target kinase activity. Mechanistically, YDH-704 coinhibits PAK1 oncogenic signaling and HDAC10 epigenetic regulation, downregulates PD-L1, and modulates the TME by reducing MDSC/Treg infiltration while enhancing CD8+ T-cell infiltration and activation. In vivo, YDH-704 exhibits favorable pharmacokinetics, robustly suppresses tumor growth and pulmonary metastasis in TNBC models, and demonstrates a clean safety profile. These findings demonstrate that dual targeting of PAK1 and HDAC10 is a promising therapeutic strategy for TNBC, and YDH-704 represents a valuable preclinical candidate for further development as an immunomodulatory antitumor agent.