Monoselective Histone Deacetylase 6 PROTAC Degrader Shows In Vivo Tractability

Autor:in

Garcha, Harsimran K.; Olaoye, Olasunkanmi; Sedighi, Abootaleb; Poloske, Daniel; Hariri, Pearla; Yu, Wenlong; Abdallah, Diaaeldin I.; Moriggl, Richard; de Araujo, Elvin D.; Gunning, P.

Abstrakt

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 DC50 of 5.81 nM after 6 h. Importantly, at concentrations up to 25 mu M, 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, CK1 alpha, 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.

Dokumententyp

Originalarbeit

DOI

10.1021/acs.jmedchem.4c02021

PubMed ID

MEDLINE:40063353