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.