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编 号：F747870
分子式：C25H24N4O2
分子量：412.48
分子式：C25H24N4O2
分子量：412.48
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CAS No: 1916505-13-9
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生物活性：
HDAC-IN-31 is a potent, selective and orally active HDAC inhibitor with IC50s of 84.90, 168.0, 442.7, >10000 nM for HDAC1, HDAC2, HDAC3, HDAC8, respectively. HDAC-IN-31 induces apoptosis and cell cycle arrests at G2/M phase. HDAC-IN-31 shows good antitumor efficacy. HDAC-IN-31 has the potential for the research of diffuse large B-cell lymphoma.
体内研究：
HDAC-IN-31 (2 mg/kg for i.v.; 10, 100 mg/kg for p.o.) shows good bioavailability with a significant dose dependent manner.HDAC-IN-31 (50, 100 mg/kg; p.o, daily for 21 consecutive days) shows good antitumor efficacy in a TMD-8 xenograft model without obvious toxicity.Pharmacokinetic Parameters of HDAC-IN-31 in mice.ParametersUnit 24 g (25 mg/kg)
Cmaxng·h·mL-13100±231
T1/2(po)h4.4±0.3
AUC0-inf(iv)ng·h·mL-11040±142
AUC0-inf(po)ng·h·mL-15180±252
MRTPOh2.6±0.4
F%39.9±2.1
ICR mouse; 2 mg/kg for i.v.; 25 mg/kg for p.o..Pharmacokinetic Parameters of HDAC-IN-31 in tumor models.ParametersUnit po (25 mg/kg) po (50 mg/kg)po (100 mg/kg)
Cmaxng·h·mL-11700±31714700±102410700±1001
AUC0-tng·h·mL-11220±2429710±3149740±230
AUC0-infng·h·mL-11230±1659730±3419770±332
MRT0-th0.750±0.0430.812±0.0231.43±0.56
MRT0-infh0.805±0.0860.821±0.0411.51±0.32
Mouse; 25, 50, 100 mg/kg for p.o..Pharmacokinetic Parameters of HDAC-IN-31 in tumor models.PK parametersUnit iv (2 mg/kg) po (10 mg/kg)po (100 mg/kg)
Cmaxng·h·mL-13960±41358300±1352
T1/2h0.427±0.0161.31±0.271.63±0.52
AUC0-infng·h·mL-11250±1322670±28657200±1047
MRTh0.402±0.0320.919±0.0520.897±0.041
CLmL·kg·min-127.2±1.2
F%45.6±1.291.8±2.3
ICR mice; 2 mg/kg for i.v.; 10, 100 mg/kg for p.o..Pharmacokinetic Parameters of HDAC-IN-31 in tumor models.PK parametersUnitMonkeyDog
iv (1 mg/kg)po (10 mg/kg)iv (1 mg/kg)po (10 mg/kg)
Cmaxng·h·mL-18520±3014740±243
T1/2h4.31±0.569.14±0.321.65±0.411.51±0.33
AUC0-infng·h·mL-115700±184253200±12412550±36515100±2004
MRTh3.41±0.128.28±0.322.26±0.412.71±0.32
CLmL·kg·min-11.35±0.216.72±0.35
VdssL·kg-10.34±0.220.55±0.04
F%27.6±2.158.9±1.2
Dogs and monkeys; 1 mg/kg for i.v., 10 mg/kg for p.o. for monkey; 1 mg/kg for i.v., 10 mg/kg for p.o. for dog.Animal Model:ICR mice
Dosage:2 mg/kg for i.v.; 25 mg/kg for p.o.(DMSO/PEG200/saline = 20:20:60, v/v/v)
Administration:I.v. or p.o.
Result:Showed high oral bioavailability (F=40%).
Animal Model:Mouse
Dosage:25, 50, 100 mg/kg
Administration:P.o.
Result:Did not exhibit a significant dose dependent for oral administration.
Animal Model:ICR mice
Dosage:2, 10, 100 mg/kg (into the form of hydrochloride)
Administration:2 mg/kg for i.v.; 10, 100 mg/kg for p.o.
Result:Showed good bioavailability with a significant dose dependent.
Animal Model:Dogs and monkeys
Dosage:1, 10 mg/kg
Administration:1 mg/kg for i.v.; 10 mg/kg for p.o.
Result:Showed good pharmacokinetic characteristics for different species.
Animal Model:5-6 weeks, female CB.17 SCID mice (TMD-8 tumor xenografts)
Dosage:50, 100 mg/kg
Administration:P.o, daily for 21 consecutive days
Result:Inhibited the tumor growth with the inhibition rate of 77% and had no significant effect on the internal organs of mice at 100 mg/kg/d.
体外研究：
HDAC-IN-31 (compound 24g) (2 μM) shows growth-inhibitory activities with the inhibition rate of 2.32%, 44.01%, 48.53%, 64.94% for TMD-8, HCT 116, A549, MDA-MB-231 cells.HDAC-IN-31 (1 μM) shows selectivity with the IC50s of 84.9, 168.0, 442.7, >10000 nM for HDAC 1, HDAC 2, HDAC 3, HDAC 8, and 81.20%, 84.43%, 88.07%, 92.34%, 96.88%, 91.98% enzyme activity for HDAC4, HDAC 5,HDAC 7, HDAC9, HDAC 6, HDAC 11, respectively.HDAC-IN-31 (2.5, 5, 7.5, 10 μM; 24 h) increases the expression of HDAC1, Ace-H3, Ace-H4, Cleaved PARP, Cleaved Caspase-3 in a dose-dependent manner.HDAC-IN-31 (0-4 μM; 24 h)induce apoptosis and cell cycle arrests in G2/M phase in a dose-dependent manner.
HDAC-IN-31 is a potent, selective and orally active HDAC inhibitor with IC50s of 84.90, 168.0, 442.7, >10000 nM for HDAC1, HDAC2, HDAC3, HDAC8, respectively. HDAC-IN-31 induces apoptosis and cell cycle arrests at G2/M phase. HDAC-IN-31 shows good antitumor efficacy. HDAC-IN-31 has the potential for the research of diffuse large B-cell lymphoma.
体内研究：
HDAC-IN-31 (2 mg/kg for i.v.; 10, 100 mg/kg for p.o.) shows good bioavailability with a significant dose dependent manner.HDAC-IN-31 (50, 100 mg/kg; p.o, daily for 21 consecutive days) shows good antitumor efficacy in a TMD-8 xenograft model without obvious toxicity.Pharmacokinetic Parameters of HDAC-IN-31 in mice.ParametersUnit 24 g (25 mg/kg)
Cmaxng·h·mL-13100±231
T1/2(po)h4.4±0.3
AUC0-inf(iv)ng·h·mL-11040±142
AUC0-inf(po)ng·h·mL-15180±252
MRTPOh2.6±0.4
F%39.9±2.1
ICR mouse; 2 mg/kg for i.v.; 25 mg/kg for p.o..Pharmacokinetic Parameters of HDAC-IN-31 in tumor models.ParametersUnit po (25 mg/kg) po (50 mg/kg)po (100 mg/kg)
Cmaxng·h·mL-11700±31714700±102410700±1001
AUC0-tng·h·mL-11220±2429710±3149740±230
AUC0-infng·h·mL-11230±1659730±3419770±332
MRT0-th0.750±0.0430.812±0.0231.43±0.56
MRT0-infh0.805±0.0860.821±0.0411.51±0.32
Mouse; 25, 50, 100 mg/kg for p.o..Pharmacokinetic Parameters of HDAC-IN-31 in tumor models.PK parametersUnit iv (2 mg/kg) po (10 mg/kg)po (100 mg/kg)
Cmaxng·h·mL-13960±41358300±1352
T1/2h0.427±0.0161.31±0.271.63±0.52
AUC0-infng·h·mL-11250±1322670±28657200±1047
MRTh0.402±0.0320.919±0.0520.897±0.041
CLmL·kg·min-127.2±1.2
F%45.6±1.291.8±2.3
ICR mice; 2 mg/kg for i.v.; 10, 100 mg/kg for p.o..Pharmacokinetic Parameters of HDAC-IN-31 in tumor models.PK parametersUnitMonkeyDog
iv (1 mg/kg)po (10 mg/kg)iv (1 mg/kg)po (10 mg/kg)
Cmaxng·h·mL-18520±3014740±243
T1/2h4.31±0.569.14±0.321.65±0.411.51±0.33
AUC0-infng·h·mL-115700±184253200±12412550±36515100±2004
MRTh3.41±0.128.28±0.322.26±0.412.71±0.32
CLmL·kg·min-11.35±0.216.72±0.35
VdssL·kg-10.34±0.220.55±0.04
F%27.6±2.158.9±1.2
Dogs and monkeys; 1 mg/kg for i.v., 10 mg/kg for p.o. for monkey; 1 mg/kg for i.v., 10 mg/kg for p.o. for dog.Animal Model:ICR mice
Dosage:2 mg/kg for i.v.; 25 mg/kg for p.o.(DMSO/PEG200/saline = 20:20:60, v/v/v)
Administration:I.v. or p.o.
Result:Showed high oral bioavailability (F=40%).
Animal Model:Mouse
Dosage:25, 50, 100 mg/kg
Administration:P.o.
Result:Did not exhibit a significant dose dependent for oral administration.
Animal Model:ICR mice
Dosage:2, 10, 100 mg/kg (into the form of hydrochloride)
Administration:2 mg/kg for i.v.; 10, 100 mg/kg for p.o.
Result:Showed good bioavailability with a significant dose dependent.
Animal Model:Dogs and monkeys
Dosage:1, 10 mg/kg
Administration:1 mg/kg for i.v.; 10 mg/kg for p.o.
Result:Showed good pharmacokinetic characteristics for different species.
Animal Model:5-6 weeks, female CB.17 SCID mice (TMD-8 tumor xenografts)
Dosage:50, 100 mg/kg
Administration:P.o, daily for 21 consecutive days
Result:Inhibited the tumor growth with the inhibition rate of 77% and had no significant effect on the internal organs of mice at 100 mg/kg/d.
体外研究：
HDAC-IN-31 (compound 24g) (2 μM) shows growth-inhibitory activities with the inhibition rate of 2.32%, 44.01%, 48.53%, 64.94% for TMD-8, HCT 116, A549, MDA-MB-231 cells.HDAC-IN-31 (1 μM) shows selectivity with the IC50s of 84.9, 168.0, 442.7, >10000 nM for HDAC 1, HDAC 2, HDAC 3, HDAC 8, and 81.20%, 84.43%, 88.07%, 92.34%, 96.88%, 91.98% enzyme activity for HDAC4, HDAC 5,HDAC 7, HDAC9, HDAC 6, HDAC 11, respectively.HDAC-IN-31 (2.5, 5, 7.5, 10 μM; 24 h) increases the expression of HDAC1, Ace-H3, Ace-H4, Cleaved PARP, Cleaved Caspase-3 in a dose-dependent manner.HDAC-IN-31 (0-4 μM; 24 h)induce apoptosis and cell cycle arrests in G2/M phase in a dose-dependent manner.
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