To determine the optimal anchor point on tubastatin A for the attachment of PROTAC linkers, as illustrated in Figure , an analysis of tubastatin A's conformation within HDAC6 reveals multiple possibilities in the capping group for linker extension, specifically at positions C1, C6, as well as on the tertiary amine. In contrast, for HDAC10 (Figure ), both C1 and C6 are buried into the pocket, which may increase the probability of collisions between the linker-attached ligand and nearby residues, such as E24 and K90. Therefore, a tubastatin A derivative featuring a flexible hexyl chain attached to the tertiary amine, designed to mimic the PROTAC linker, was docked into the catalytic pockets of both HDAC6 and HDAC10 (Figure and). Notably, this derivative aligns well with the co-crystal structures of tubastatin A bound to both HDAC6 and HDAC10, with the hexyl chain extending beyond the pocket boundaries in both cases. Consequently, the tertiary amine in the capping group of tubastatin A was identified as an optimal anchor point.