Delayed and Prolonged Histone Hyperacetylation with a Selective HDAC1/HDAC2 Inhibitor

Abstract

The identification and in vitro and in vivo characterization of a potent SHI-1:2 are described. Kinetic analysis indicated that biaryl inhibitors exhibit slow binding kinetics in isolated HDAC1 and HDAC2 preparations. Delayed histone hyperacetylation and gene expression changes were also observed in cell culture, and histone acetylation was observed in vivo beyond disappearance of drug from plasma. In vivo studies further demonstrated that continuous target inhibition was well tolerated and efficacious in tumor-bearing mice, leading to tumor growth inhibition with either once-daily or intermittent administration.

Development and Biological Evaluation of the First Highly Potent and Specific Benzamide-Based Radiotracer [18F]BA3 for Imaging of Histone Deacetylases 1 and 2 in Brain

“…1 H-NMR (400 MHz, DMSO- d 6 ) δ 8.34 (s, 1H), 7.44 (dd, J = 5.1, 1.2 Hz, 1H), 7.32–7.24 (m, 2H), 7.08 (dd, J = 5.1, 3.6 Hz, 1H), 6.98 (d, J = 2.2 Hz, 1H), 6.84 (dd, J = 8.2, 2.2 Hz, 1H), 5.01 (s, 2H), 1.47 (s, 9H); 13 C-NMR (101 MHz, DMSO- d 6 ) δ 153.48, 144.01, 141.20, 130.18, 128.21, 124.55, 123.51, 122.42, 113.65, 112.40, 78.83, 28.15 (in accordance with literature [ 49 ]).…”

“…First of all, the amino group was treated with di-tert-butyl dicarbonate (Boc 2 O) and catalytic amounts of N,N-dimethyl-4-aminopyridine (DMAP) to afford the bis-Boc-protected intermediate followed by cleavage of one Boc group using trifluoroacetic acid (TFA) to give tert-butyl (4-bromo-2-nitrophenyl)carbamate (1) in a total yield of 95%. Under these conditions it was possible to achieve higher yields with this two-step synthesis compared with the reported yields [49][50][51][52][53] using a one-step synthesis. Subsequently, 1 was reacted with 2-/3-thienyl-, 2-/3-furanyl-or para-fluoro-phenylboronic acid in a Suzuki cross coupling reaction with tetrakis(triphenylphosphine)palladium(0) (Pd(PPh 3 ) 4 ) in 1,4-dioxane/water (7:3, v/v) to provide the corresponding compounds 2a-e in very good yields (90-96%).…”

“…Subsequently, 1 was reacted with 2-/3-thienyl-, 2-/3-furanyl- or para -fluoro-phenylboronic acid in a Suzuki cross coupling reaction with tetrakis(triphenylphosphine)palladium(0) (Pd(PPh 3 ) 4 ) in 1,4-dioxane/water (7:3, v / v ) to provide the corresponding compounds 2a – e in very good yields (90–96%). In the first approach, the reduction in the aromatic nitro group was carried out under hydrogen atmosphere with palladium on carbon and afforded 3a – c in quantitative yields [ 49 ]. Using the same procedure for the 3-furan-containing compound 2e , the desired aniline product could not be obtained.…”

An Isochemogenic Set of Inhibitors To Define the Therapeutic Potential of Histone Deacetylases in β-Cell Protection

“…Therefore, we set out to design a tool kit of highly potent and selective class I HDACi to differentiate specific isoforms, using a synthetically efficient and rational design-based approach to exploit the clinically experienced ortho -aminoanilide HDACi, CI-994 (tacedinaline). We chose this chemical class and this compound because they (1) are sub-Class I-selective (HDAC1,2,3, Supplementary Figure S1 and Table S1,2), (2) possess excellent drug-like properties in humans, (3) are relatively well tolerated in humans, (4) are obtained via an efficient, modular chemical synthesis, (5) are potent, slow binders, − and (6) have previously demonstrated selectivity among HDAC1, 2, and 3. ,− Using CI-994 as our core chemical scaffold, a set of matched isochemogenic inhibitors was designed, synthesized, and characterized for their ability to differentiate among the class I HDACs. By analogy to genetics, isochemogenic inhibitors are based on a common chemical scaffold, akin to a common genetic background, with minimal structural point changes (“mutations”), to impart differential biological activity across closely related targets.…”

1,25(OH)2D3 inhibits the progression of hepatocellular carcinoma via downregulating HDAC2 and upregulating P21(WAFI/CIP1)

“…HDAC2 is a major deacetylase, and its expression is inversely associated with changes in the acetylation state of histone H4K5. RNA interference-mediated gene silencing of HDAC2 leads to hyperacetylation of histone H4 and a developmental delay, although the levels of HDAC3 remain high (20,21). Increased expression levels of p21(WAF1/Cip1) may contribute to the observed developmental delay.…”