Discovery of Highly Potent and Orally Bioavailable Histone Deacetylase 3 Inhibitors as Immunomodulators and Enhancers of DNA-Damage Response in Cancer Therapy

Histone deacetylase 3 (HDAC3) is a well-established target for cancer therapy. Herein, we developed LSQ-28 as a novel HDAC3 inhibitor, which exhibited high HDAC3 inhibitory activity (IC50 = 42 nM, SI > 161) and displayed potent antiproliferative activity against four cancer cells and further demonstrated excellent antimigratory, anti-invasive, and antiwound healing activities. Further studies revealed that LSQ-28 induced a dose-dependent increase in Ac-H3 expression and promoted the degradation of PD-L1. Additionally, LSQ-28 enhanced the DNA damage response induced by PARP inhibitor, as evidenced by regulated expression of PARP1 and γ-H2AX. Notably, LSQ-28 also possessed favorable pharmacokinetic properties with significant oral bioavailability (F = 95.34%). Importantly, the combination of LSQ-28 with the PD-L1 inhibitor NP-19 could enhance antitumor immune response (TGI = 80%). When combined with olaparib, LSQ-28 significantly enhanced the in vivo tumor–suppression activity (TGI = 91%). Collectively, LSQ-28 represents a promising HDAC3 inhibitor for further exploration in cancer therapeutic strategies.组蛋白去乙酰化酶3（Histone deacetylase 3, HDAC3）是已被广泛证实的癌症治疗靶点。本研究开发了新型HDAC3抑制剂LSQ-28，该化合物展现出优异的HDAC3抑制活性（半数抑制浓度IC50=42 nM，选择指数SI>161），对四种癌细胞均表现出强效的抗增殖活性；同时还具备出色的抗迁移、抗侵袭及伤口愈合抑制活性。后续研究表明，LSQ-28可诱导乙酰化组蛋白H3（Ac-H3）的表达呈剂量依赖性升高，并促进程序性死亡配体1（PD-L1）的降解。此外，LSQ-28能够增强聚ADP核糖聚合酶（PARP）抑制剂诱导的DNA损伤应答，这一效应可通过PARP1与磷酸化组蛋白H2AX（γ-H2AX）的表达调控得到验证。值得注意的是，LSQ-28还具有良好的药代动力学特性，口服生物利用度显著（F=95.34%）。重要的是，LSQ-28与PD-L1抑制剂NP-19联合使用可增强抗肿瘤免疫应答（肿瘤生长抑制率TGI=80%）；而与奥拉帕利（olaparib）联用时，LSQ-28可显著提升体内抗肿瘤活性（TGI=91%）。综上，LSQ-28是一款极具开发前景的HDAC3抑制剂，有望在癌症治疗策略中开展进一步探索。