Development of novel quinoline derivatives as selective HDAC6 inhibitors exhibiting multiple anticancer effects.

Histone deacetylase 6 (HDAC6) is an important player in the cellular process. Overexpression of HDAC6 is associated with tumorigenesis and becomes a major cause of death in patients with cancers. Herein, Optimization of the lead compound MPT0G211 yielded a potent HDAC6 inhibitor, P21, with significantly improved potency and selectivity over other isoforms Western blot analysis further confirmed that the compound selectively increased the acetylation levels of α-tubulin without affecting histone H3. Furthermore, compound P21 exhibited potent anti-proliferative, anti-invasive, and anti-angiogenic activities, alongside the induction of apoptosis and cell cycle arrest. Notably, it demonstrated significant anti-proliferative efficacy in vivo in a patient-derived xenograft (PDX) mouse model. Collectively, the results strongly encourage further development of P21 as an anticancer agent.