Monoselective Histone Deacetylase 6 PROTAC Degrader Shows <i>In Vivo</i> Tractability
Harsimran Kaur Garcha, Olasunkanmi O. Olaoye, Abootaleb Sedighi, Daniel Pölöske, Pearla Hariri, Wenlong Yu, Diaaeldin I. Abdallah, Richard Moriggl, Elvin D. de Araujo, Patrick T. Gunning
Abstract
Herein, we report a potent HDAC6 PROTAC, TO-1187, which selectively degrades HDAC6 in cellulo and demonstrates in vivo efficacy. The design of TO-1187 was achieved by linking our previously reported HDAC6 inhibitor, TO-317, to the cereblon (CRBN) E3 ligase ligand, pomalidomide. TO-1187 achieved monoselective HDAC6 degradation in human multiple myeloma cells, MM.1S, with a D max of 94% and a DC 50 of 5.81 nM after 6 h. Importantly, at concentrations up to 25 μM, TO-1187 exhibited no cellular degradation of other HDACs. Proteomic evaluation confirmed a highly selective proteome-wide degradation profile, with HDAC6 the only protein observed to be depleted. Notably, TO-1187 did not impact the abundance of well-known CRBN neosubstrates, like IKZF1, IKZF3, CK1α, SALL4, and GSPT1. In vivo evaluation confirmed that TO-1187 efficiently degraded HDAC6 in mouse tissues, measured 6 h after intravenous injection. In summary, TO-1187 represents a viable candidate for advanced preclinical evaluation of HDAC6 biology.