Development and Characterization of the First Selective Class IIb Histone Deacetylase Degraders

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Drug Discovery

Background:

• Proteolysis-targeting chimeras (PROTACs) represent a novel therapeutic strategy for targeted protein degradation.
• Histone deacetylases (HDACs) are implicated in various diseases, making them attractive therapeutic targets.

Purpose of the Study:

• To design, synthesize, and evaluate the first-in-class selective degraders of class IIb histone deacetylases (HDACs) 6 and 10.
• To develop a chemical tool for targeted protein knockdown with potential applications in cancer therapy.

Main Methods:

• Utilized PROTAC technology by conjugating a dual HDAC6/10 inhibitor (tubastatin A analog) with cereblon recruiters (pomalidomide and phenylglutarimides).
• Synthesized and biologically evaluated novel PROTAC compounds.
• Assessed compound selectivity against different HDAC classes (I, IIa, IIb) and evaluated cytotoxicity in cancer cell lines.

Main Results:

• Discovered AP1, a potent degrader of HDAC6 (DC50 = 13 nM) and HDAC10 (DC50 = 29 nM).
• Demonstrated AP1's selectivity for class IIb HDACs, showing no degradation of HDAC1/8 (class I) or HDAC4/7 (class IIa).
• Confirmed AP1's lack of histone H3 hyperacetylation, indicating specific target engagement.
• Observed low cytotoxicity of AP1 against hematological and solid cancer cell lines.

Conclusions:

• AP1 is the first selective degrader identified for class IIb HDACs (HDAC6 and HDAC10).
• AP1 exhibits high potency and selectivity, making it a valuable tool compound.
• AP1's favorable cytotoxicity profile suggests its potential utility in chemical knockdown strategies for diseases involving class IIb HDACs.