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HDAC-IN-56 ((S)-17b) is an orally active class I histone deacetylase (HDAC) inhibitor with IC50 values of 56.0 ± 6.0, 90.0 ± 5.9, 422.2 ± 105.1, >10000 nM for HDAC1, HDAC2, HDAC3, and HDAC4-11, respectively. HDAC-IN-56 has potent inhibitory activity while strongly increasing intracellular levels of acetylhistone H3 and P21 and effectively inducing G1 cell cycle arrest and apoptosis.HDAC-IN-56 has antitumor activity [1]. | [in vivo]
HDAC-IN-56 (10-80 mg/kg/d, p.o., one month) cause no significant change of body weight, even at high dose of 80 mg/kg per day, the mice can tolerate with the descended body weight compared with the control[1].
HDAC-IN-56 (SD: 10, 20 mg/kg ; ICR: 20, 40 mg/kg, p.o.) represent a favorable pharmacokinetic profile with an oral bioavailability of 47.7% in ICR mice and 39.5% in SD rat, respectively[1].
HDAC-IN-56 (20-60 mg/kg, p.o.) inhibit the tumor growth of MC38 cells in nude mice as expected, when inoculate in immunocompetent C57BL/6 mice show more significant tumor growth inhibition at the same doses, which implie that the immune system may be engaged and somehow activated gain stronger antitumor effect[1].
In vivo pharmacokinetics of HDAC-IN-56 (compuond (S)-17b) in ICR mice and SD rat[1]
| | | | ICR mice | | | | | | | | SD rat | | | | | | (S)-17b | dose (mg/kg) | CL (mL/min/kg) | Vss (L/kg) | T1/2(h) | AUC0-t(h x ng/mL) | Cmax (ng/mL) | Tmax (h) | F (%) | dose (mg/kg) | CL (mL/min/kg) | Vss (L/kg) | T1/2(h) | AUC0-t(h x ng/mL) | Cmax (ng/mL) | Tmax (h) | F (%) | | iv | 20 | 64.4 ± 10.3 | 5.3 ± 1.2 | 3.6 ± 0.3 | 5269 ± 924 | | | | 10 | 34.3 ± 8.6 | 4.1 ± 0.8 | 1.5 ± 0.2 | 4935 ± 1068 | | | | | po | 40 | | | 2.5 ± 0.3 | 5031 ± 441 | 1963 ± 335 | 0.83 ± 0.29 | 47.7 | 20 | | | 2.3 ± 0.6 | 3895 ± 141 | 1086 ± 16 | 2.00 | 39.5 |
| Animal Model: | Male SD rats or ICR mice[1] | | Dosage: | 10, 20 mg/kg ; ICR: 20, 40 mg/kg | | Administration: | Male SD rats or ICR mice (n = 6) were fasted for 12 h before administration and remained fasting for 2 h. SD rats were received 10 and 20 mg/kg via intravenously injection (iv) and oral administration (po), respectively, and ICR mice were received 20 and 40 mg/kg via intravenously injection (iv) and oral administration (po), respectively. | | Result: | Epresented a favorable pharmacokinetic profile with an oral bioavailability of 47.7% in ICR mice and 39.5% in SD rat, respectively |
| Animal Model: | SKM-1 or MC-38 cells xenograft model[1] | | Dosage: | 20, 40, 60 mg/kg | | Administration: | Oral gavage (p.o.). | | Result: | Inhibited the tumor growth of MC38 cells in nude mice.
Showed more significant tumor growth inhibition at the same doses, which implie that the immune system may be engaged and somehow activated HDAC-IN-56 to gain stronger antitumor effect. |
| [IC 50]
HDAC1: 56.0 nM (IC50); HDAC2: 90.0 nM (IC50); HDAC3: 422.2 nM (IC50) | [References]
[1] Li D, et al. Discovery of (S)-N-(2-Amino-4-fluorophenyl)-4-(1-(3-(4-((dimethylamino)methyl)phenyl)-6-oxopyridazin-1(6H)-yl)ethyl) benzamide as Potent Class I Selective HDAC Inhibitor for Oral Anticancer Drug Candidate. J Med Chem. 2023 May 25;66(10):7016-7037. DOI:10.1021/acs.jmedchem.3c00525 |
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