Pracinostat is a potent histone deacetylase (HDAC) inhibitor, with IC50s of 40-140 nM, used for cancer research.
Description :
Pracinostat (SB939) is a potent, orally active HDAC inhibitor that potently inhibits class I, II, and IV HDACsw with Ki of 15-100 nM, inhibits HDAC1 with IC50 of 77 nM; shows cellular potency against COLO 205 cells with IC50 of 0.56 uM; Pracinostat (SB939) is highly efficacious in in vivo tumor models (HCT-116, PC-3, A2780, MV4-11, Ramos), and has high and dose-proportional oral exposures and very good ADME, safety, and pharmaceutical properties; also is a potent inhibitor of the growth of Plasmodium falciparum asexual-stage parasites in vitro (IC50=100 to 200 nM), causing hyperacetylation of parasite histone and nonhistone proteins.
Blood Cancer
SB939 has a 100-fold greater selectivity for HDACs than for Zn-binding non-HDAC enzymes, receptors, and ion channels. SB939 is a potent inhibitor of HDAC class I isoenzymes, HDAC1, HDAC2, HDAC3 and HDAC8 with the IC50 values ranging from 43 nM to 140 nM. SB939 inhibits HDAC class II isoenzymes , HDAC4, HDAC5, HDAC7, HDAC9 and HDAC10 significantly with the IC50 values ranging from 40 nM to 137 nM, with the exception of HDAC6 which shows IC50 of 1008 nM. It markedly inhibits HDAC11 of the HDAC class IV enzymes with IC50 of 93 nM, but shows no inhibitory activity against SIRT 1 of the class III HDACs. SB939 shows significant antiproliferative activity against a wide variety of tumor cell lines, especially Leukemia cells and cutaneous T-cell Lymphoma cells with IC50 values ranging from 50 nM (H9 cells) to 170 nM (HEL92.1.7 cells). [1]Pracinostat (SB939, compound 3) inhibits CYP2C19 with IC50 of 5.78 μM. SB939 shows potent activities against A2780, COLO 205, HCT-116, and PC-3 cell lines, with IC50s of 0.48 ± 0.21, 0.56 ± 0.08, 0.48 ± 0.27, and 0.34 ± 0.06[2]. Pracinostat downregulates JAK and FLT3 signaling in JAK2V617F and FLT-ITD cell lines, and shows synergy in combination with pacritinib. Pracinostat and pacritinib show in vitro synergy on STAT signaling and apoptosis. Pracinostat potently inhibits proliferation of different AML subtypes as a single agent and is synergistic with pacritinib in JAK2V617F or FLT3-ITD AML cell lines[3].
Administration of SB939 (25 mg/kg to 100 mg/kg) displays a dose-dependent antitumor efficacy in a xenograft mice model of human colorectal cancer (HCT-116). This is approximately twice as efficacious as SAHA: SB939 causing a tumor growth inhibition of 94% versus 48% by SAHA with both at the maximum tolerated dose. Oral administration of SB939 at a dose of 50 mg/kg or 75 mg/kg in the APCmin genetic mice model of early-stage colon cancer markedly reduces the number of tumors , decreases cumulative hemocult scores and increases hematocrit values more effectively than 5-fluorouracil. [1]