Exploring Structural Determinants of Inhibitor Affinity and Selectivity in Complexes with Histone Deacetylase 6

Inhibition of histone deacetylase 6 (HDAC6) has emerged
as a promising
therapeutic strategy for the treatment of cancer, chemotherapy-induced
peripheral neuropathy, and neurodegenerative disease. The recent X-ray
crystal structure determination of HDAC6 enables an understanding
of structural features directing affinity and selectivity in the active
site. Here, we present the X-ray crystal structures of five HDAC6–inhibitor
complexes that illuminate key molecular features of the inhibitor
linker and capping groups that facilitate and differentiate binding
to HDAC6. In particular, aromatic and heteroaromatic linkers nestle
within an aromatic cleft defined by F583 and F643, and different aromatic
linkers direct the capping group toward shallow pockets defined by
the L1 loop, the L2 loop, or somewhere in between these pockets. These
results expand our understanding of factors contributing to the selective
inhibition of HDAC6, particularly regarding interactions that can
be targeted in the region of the L2 pocket.