PROTAC HDAC degrader-2 TFA is a selective class IIb dual histone deacetylase ( HDAC6 and HDAC10 ) PROTAC degrader, with DC50 values of 13 nM and 29 nM against HDAC6 and HDAC10, respectively. It does not degrade class I ( HDAC1/8 ) and class IIa ( HDAC4/7 ) histone deacetylases [1]. (Pink: HDAC6 and HDAC10 ligand; Blue: Cereblon ligand; Black: linker).
In Vitro, PROTAC HDAC degrader-2 (AP1) TFA potently inhibits purified HDAC6 and HDAC10 enzymes with IC50 values of 0.040 μM and 0.022 μM, respectively[1]. PROTAC HDAC degrader-2 TFA engages cellular CRBN in HEK293T cells stably expressing NanoLuc-CRBN with an IC50 of 7.5 μM, an upper estimate due to autofluorescence interference[1]. PROTAC HDAC degrader-2 (50 nM, 1 μM; up to 1440 min) TFA shows high stability in human plasma at 1 μM, remaining above 85% intact for up to 1440 min[1]. PROTAC HDAC degrader-2 (1-5 μM; 24 h) TFA potently and selectively degrades HDAC6 and HDAC10 in MM.1S cells, with DC50 values of 13 nM and 29 nM, respectively, and no off-target degradation of class I or class IIa HDAC subtypes at 1 μM for 24 h[1]. PROTAC HDAC degrader-2 (1 μM; 24 h) TFA does not induce histone H3 hyperacetylation and shows minimal effects on acetylated α-tubulin in MM.1S cells treated with 1 μM for 24 h, confirming its class IIb HDAC selectivity[1].
References:
[1]. Zhai S, et al. Development and Characterization of the First Selective Class IIb Histone Deacetylase Degraders. Journal of medicinal chemistry. 2025 Jul 10;68(13):13793-13821.
In Vitro, PROTAC HDAC degrader-2 (AP1) TFA potently inhibits purified HDAC6 and HDAC10 enzymes with IC50 values of 0.040 μM and 0.022 μM, respectively[1]. PROTAC HDAC degrader-2 TFA engages cellular CRBN in HEK293T cells stably expressing NanoLuc-CRBN with an IC50 of 7.5 μM, an upper estimate due to autofluorescence interference[1]. PROTAC HDAC degrader-2 (50 nM, 1 μM; up to 1440 min) TFA shows high stability in human plasma at 1 μM, remaining above 85% intact for up to 1440 min[1]. PROTAC HDAC degrader-2 (1-5 μM; 24 h) TFA potently and selectively degrades HDAC6 and HDAC10 in MM.1S cells, with DC50 values of 13 nM and 29 nM, respectively, and no off-target degradation of class I or class IIa HDAC subtypes at 1 μM for 24 h[1]. PROTAC HDAC degrader-2 (1 μM; 24 h) TFA does not induce histone H3 hyperacetylation and shows minimal effects on acetylated α-tubulin in MM.1S cells treated with 1 μM for 24 h, confirming its class IIb HDAC selectivity[1].
References:
[1]. Zhai S, et al. Development and Characterization of the First Selective Class IIb Histone Deacetylase Degraders. Journal of medicinal chemistry. 2025 Jul 10;68(13):13793-13821.