PROTAC HDAC6 degrader 1

PROTAC HDAC6 degrader (Compound A6) is a potent and selective PROTAC HDAC6 degrader with a DC50 of 3.5 nM. PROTAC HDAC6 degrader shows promising antiproliferative activity via inducing apoptosis in myeloid leukemia cell lines[1].

Signaling Pathways >> Apoptosis >> Apoptosis

Research Areas >> Cancer

Signaling Pathways >> PROTAC >> PROTAC

Signaling Pathways >> Cell Cycle/DNA Damage >> HDAC

Signaling Pathways >> Epigenetics >> HDAC

HDAC6:3.5 nM (DC50)

HDAC6:4.86 nM (IC50)

HDAC1:0.1 μM (IC50)

PROTAC HDAC6 degrader (Compound A6) (0.1-10 μM; 6 h) does not degrade HDAC1 but displays inhibitory activity toward HDAC1. PROTAC HDAC6 degrader demonstrates potent HDAC6 degradation as well as hyperacetylation of α-tubulin in U266 and HL-60 cells, confirming that the activity is not restricted to leukemia cell lines[1]. PROTAC HDAC6 degrader (0.5-50 μM) inhibits leukemia cells viability with log IC50 values of 1.2-1.7 μM[1]. PROTAC HDAC6 degrader (8-24 μM; 48 h) induces MOLM13 cell apoptosis and arrests cell cycle at sub-G1 phase[1]. Western Blot Analysis[1] Cell Line: HL-60 cells Concentration: 100 nM, 1 μM, 10 μM Incubation Time: 6 h Result: Degraded HDAC6 but not HDAC1. Induced hyperacetylation of α-tubulin and caused hyperacetylation of histone H3. Cell Viability Assay[1] Cell Line: Acute myeloid leukemia or AML (HL-60, Kasumi, THP-1, HL-60, SKNO1, and MOLM13) and B-cell acute lymphoblastic leukemia or B-ALL (REH and 697) Concentration: 0.5-50 μM Incubation Time: 72 h Result: Inhibited cell viability with log IC50 values of 1.2-1.7 μM. Apoptosis Analysis[1] Cell Line: MOLM13 Concentration: 8, 16 and 24 μM Incubation Time: 48 h Result: Induced caspase 3/7-dependent apoptosis in dose-dependent fashion. Cell Cycle Analysis[1] Cell Line: MOLM13 Concentration: 8, 16 and 24 μM Incubation Time: 48 h Result: Induced a dose-dependent increase in the sub-G1 fraction with a concomitant reduction of cell population in G2/M phase.

[1]. Sinatra L, et al. Solid-Phase Synthesis of Cereblon-Recruiting Selective Histone Deacetylase 6 Degraders (HDAC6 PROTACs) with Antileukemic Activity. J Med Chem. 2022 Dec 22;65(24):16860-16878.