Development of a Potent and Isoform-Selective HDAC11 Inhibitor with Anti-Tumor Efficacy against Non-Small Cell Lung Cancer

Targeting histone deacetylase 11 (HDAC11) represents a promising therapeutic strategy, yet developing selective inhibitors for solid tumors remains a formidable challenge. Herein, we describe the rational lead optimization of a novel series of indole-based hydroxamic acids. Guided by our previous lead PB94, a systematic, multiparameter optimization of the core, linker, and cap regions was conducted to specifically target HDAC11. This campaign yielded compound YP200, which incorporates a precisely positioned secondary amine linker and an adamantane surface-recognition cap. YP200 exhibited exceptional HDAC11 inhibitory potency (IC50 = 0.058 ± 0.01 μM) and good selectivity (>103-fold) over other HDACs. Furthermore, YP200 demonstrated good in vivo anti-tumor efficacy in a non-small cell lung cancer (NSCLC) patient-derived xenograft model. These findings validate YP200 as a promising HDAC11-targeted therapeutic candidate, significantly expanding the therapeutic arsenal for solid tumors.