Challenging triple negative breast cancer through HDAC6 selective inhibition: Novel cap-group identification, structure-activity relationships, computational and biological studies

Triple negative breast cancer (TNBC) stands out among breast cancers subtypes for its high aggressiveness and invasiveness. Compelling new evidence pointed out the role of epigenetic modifications in TNBC, with recent studies demonstrating that approximately 30 % of human breast cancers could potentially benefit from histone deacetylase 6 (HDAC6) inhibitor therapy. We herein disclose a novel class of spiro-fused compounds acting as potent and selective HDAC6 inhibitors. Structure-based optimization led to derivatives 23c and 24c with high potency and selectivity towards HDAC6 in vitro and in cell-based settings. Following our observation that mRNA expression level of HDAC6 was significantly higher in MDA-MB-231, we have evaluated the effect of the compounds on cell viability. Moreover, we have unveiled for compounds 23c and 24c the involvement of the autophagic machinery in cell death induction. Scratch assay revealed for the newly conceived compounds a very potent effect on inhibiting the migration process in MDA-MB-231 cells. Our results underscore the key role of HDAC6 in TNBC progression, providing a solid groundwork to reshape TNBC therapy.