Quisinostat

Quisinostat (JNJ-26481585) is an orally available, potent HDAC inhibitor with an IC50 of 0.11 nM for HDAC1.

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

Signaling Pathways >> Epigenetics >> HDAC

Research Areas >> Cancer

HDAC1:0.11 nM (IC50)

HDAC2:0.33 nM (IC50)

HDAC11:0.37 nM (IC50)

HDAC10:0.46 nM (IC50)

HDAC5:3.69 nM (IC50)

HDAC8:4.26 nM (IC50)

HDAC3:4.86 nM (IC50)

HDAC9:32.1 nM (IC50)

HDAC6:76.8 nM (IC50)

HDAC7:119 nM (IC50)

Quisinostat exerts broad-spectrum antiproliferative activity against a wide panel of cancer cell lines including lung, colon, breast, prostate, and ovarian cell lines at nanomolar concentrations. JNJ-26481585 shows activity toward all HDAC enzymes tested with highest potency in vitro observed toward recombinant HDAC1 (IC50, 0.11±0.03 nM), which is comparable with the potency observed toward HDAC1-immunoprecipitated complexes from tumor cells (IC50, 0.16±0.02 nM). Lowest in vitro potency is observed toward HDAC6, 7 and 9 (IC50, 32.1-119 nM) [1].

JNJ-26481585 induces continuous H3 acetylation in tumor tissue in vivo. JNJ-26481585, a “second-generation” HDAC inhibitor with prolonged pharmacodynamic response in vivo. In agreement with the hypothesis, JNJ-26481585 showed superior efficacy compared with both standard of care agents and first-generation HDAC inhibitors in preclinical tumor models. These studies suggest that an HDAC inhibitor with continuous pharmacodynamic activity may show activity in solid tumor malignancies[1].

JNJ-26481585 is dissolved in DMSO as 5mM stock solution and diluted with appropriate medium. Human A2780 ovarian tumor cells (107 cells/mouse) are injected s.c. into the inguinal region of male athymic nu/nu CD-1 mice. When palpable tumors are obtained, mice are treated once daily with vehicle (10% hydroxypropyl-β-cyclodextrin) or JNJ-26481585 at 10 mg/kg i.p., and tumor and plasma is harvested at day 1 and at day 7 at the indicated time points (5 mice/point). Levels of AcH3 are determined using a quantitative ELISA (300 ng tumor protein/well) and described on the basis of an indirect response pharmacodynamic model[1].

[1]. Arts J, et al. JNJ-26481585, a novel "second-generation" oral histone deacetylase inhibitor, shows broad-spectrum preclinical antitumoral activity. Clin Cancer Res. 2009 Nov 15;15(22):6841-51.

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