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Published on: June 13, 2014
Design, Synthesis, and Biological Evaluation of Novel PAK1/HDAC10 Dual Inhibitors That Activate Antitumor Immunity
Weiji Chen1,2, Xiaoling Cheng1,2, Xi Zhao1,3
1School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen 518060, China.
Abstract:
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.
Insights
Triple-negative breast cancer (TNBC) is challenging due to limited targets. A novel dual PAK1/HDAC10 inhibitor, YDH-704, shows promise by suppressing cancer growth and enhancing anti-tumor immunity.
Area of Science:
- Oncology
- Pharmacology
- Immunology
Background:
- Triple-negative breast cancer (TNBC) presents significant therapeutic challenges, including a lack of specific targets and an immunosuppressive tumor microenvironment (TME).
- Existing treatments like immune checkpoint inhibitors (ICIs) have limited efficacy in TNBC.
- The combination of oncogenic signaling and epigenetic dysregulation contributes to TNBC's aggressive nature.
Purpose of the Study:
- To design and synthesize novel dual inhibitors targeting both PAK1 and HDAC10 for TNBC treatment.
- To evaluate the efficacy of the lead compound YDH-704 in preclinical TNBC models.
- To investigate the immunomodulatory effects of YDH-704 on the tumor microenvironment.
Main Methods:
- Rational drug design and chemical synthesis of dual PAK1/HDAC10 inhibitors.
- In vitro biochemical assays to determine potency and selectivity of YDH-704.
- In vitro mechanistic studies assessing PD-L1 expression and immune cell modulation (MDSC, Treg, CD8+ T cells).
- In vivo studies in TNBC models to evaluate pharmacokinetics, tumor growth inhibition, metastasis suppression, and safety.
Main Results:
- YDH-704 demonstrated nanomolar potency against PAK1 and HDAC10 with high selectivity for HDAC10.
- YDH-704 effectively suppressed oncogenic PAK1 signaling and HDAC10 epigenetic activity.
- The compound downregulated PD-L1, reduced suppressive immune cells (MDSC, Treg), and enhanced cytotoxic CD8+ T cell infiltration and activation within the TME.
- In vivo, YDH-704 exhibited favorable pharmacokinetics, significantly inhibited tumor growth and metastasis, and showed a good safety profile.
Conclusions:
- Dual inhibition of PAK1 and HDAC10 represents a viable therapeutic strategy for TNBC.
- YDH-704 is a promising preclinical candidate for TNBC, acting as an immunomodulatory antitumor agent.
- Targeting both oncogenic signaling and the TME offers a novel approach to overcome TNBC treatment resistance.
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