PROTAC HDAC4 Degrader-2 is a class IIa selective negative control for HDAC4 PROTAC degraders, with an IC50 of 0.15 μM against HDAC4 and a cellular IC50 of 0.18 μM. PROTAC HDAC4 Degrader-2 fails to effectively recruit the VHL E3 ligase, and thus does not induce significant degradation of HDAC4 protein [1]. (Pink: HDAC4 ligand; Blue: VHL ligand; Black: linker ).
In Vitro, PROTAC HDAC4 Degrader-2 (Compound 12) inhibits recombinant HDAC4 catalytic activity with an IC50 of 0.15 μM[1]. PROTAC HDAC4 Degrader-2 (24 h) inhibits cellular class IIa HDAC activity in Jurkat E6-1 cells with an IC50 of 0.18 μM and is selective over class I HDACs[1]. PROTAC HDAC4 Degrader-2 (0.05 nM-10 μM; 24 h) does not significantly degrade HDAC4 in Jurkat E6-1 cells, with a DC50 >10,000 nM and only 50% maximum degradation at 10 μM[1]. PROTAC HDAC4 Degrader-2 (0.05 nM-10 μM; 24 h) fails to induce HDAC4 degradation in Jurkat E6-1 cells across concentrations ranging from 0.05 nM to 10 μM after 24 hours of treatment[1].
References:
[1]. Macabuag N, Esmieu W, Breccia P, et al.. Developing HDAC4-Selective Protein Degraders To Investigate the Role of HDAC4 in Huntington's Disease Pathology. Journal of medicinal chemistry. 2022 Sep 22;65(18):12445-12459.
In Vitro, PROTAC HDAC4 Degrader-2 (Compound 12) inhibits recombinant HDAC4 catalytic activity with an IC50 of 0.15 μM[1]. PROTAC HDAC4 Degrader-2 (24 h) inhibits cellular class IIa HDAC activity in Jurkat E6-1 cells with an IC50 of 0.18 μM and is selective over class I HDACs[1]. PROTAC HDAC4 Degrader-2 (0.05 nM-10 μM; 24 h) does not significantly degrade HDAC4 in Jurkat E6-1 cells, with a DC50 >10,000 nM and only 50% maximum degradation at 10 μM[1]. PROTAC HDAC4 Degrader-2 (0.05 nM-10 μM; 24 h) fails to induce HDAC4 degradation in Jurkat E6-1 cells across concentrations ranging from 0.05 nM to 10 μM after 24 hours of treatment[1].
References:
[1]. Macabuag N, Esmieu W, Breccia P, et al.. Developing HDAC4-Selective Protein Degraders To Investigate the Role of HDAC4 in Huntington's Disease Pathology. Journal of medicinal chemistry. 2022 Sep 22;65(18):12445-12459.