Monoselective Histone Deacetylase 6 PROTAC Degrader Shows In Vivo Tractability

Area of Science:

• Chemical Biology
• Molecular Biology
• Pharmacology

Background:

• Histone deacetylase 6 (HDAC6) is implicated in various cellular processes and diseases.
• Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) is an emerging therapeutic strategy.

Purpose of the Study:

• To design and characterize a novel PROTAC, TO-1187, for selective degradation of HDAC6.
• To evaluate the in vitro and in vivo efficacy and selectivity of TO-1187.

Main Methods:

• PROTAC design by linking an HDAC6 inhibitor (TO-317) to a cereblon (CRBN) ligand (pomalidomide).
• In vitro assessment of HDAC6 degradation in human multiple myeloma cells (MM.1S).
• Proteomic analysis to determine proteome-wide degradation profile and selectivity.
• In vivo evaluation of HDAC6 degradation in mouse tissues.

Main Results:

• TO-1187 achieved potent and monoselective HDAC6 degradation in MM.1S cells (DC50 = 5.81 nM).
• No degradation of other HDACs or known CRBN neosubstrates was observed up to 25 μM.
• Proteomic profiling confirmed high selectivity, with only HDAC6 depletion.
• TO-1187 demonstrated efficient in vivo HDAC6 degradation in mouse tissues post-injection.

Conclusions:

• TO-1187 is a potent and selective HDAC6-targeting PROTAC with demonstrated in vitro and in vivo efficacy.
• The compound exhibits a favorable selectivity profile, avoiding degradation of other HDACs and CRBN neosubstrates.
• TO-1187 is a promising candidate for further preclinical development and investigation of HDAC6 biology.