体外研究
(In Vitro) |
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[1].
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[1].
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[1].
HDAC-IN-31 (0-4 µM; 24 h)induce apoptosis and cell cycle arrests in G2/M phase in a dose-dependent manner[1].
Shanghai Jinpan Biotech Co Ltd has not independently confirmed the accuracy of these methods. They are for reference only.
Cell Proliferation Assay[1]
| Cell Line: |
MDA-MB-231, A549, NCI-H460, HCT-116,SK-OV-3, HT-29, COLO 678, NCI-H441, 22Rv1, 786-O, TMD-8, DOHH-2, CCRF-CEM, SU-DHL-2, REC-1, MOLT-4, HUT-78, RS4;11 cells |
| Concentration: |
0-20 µM |
| Incubation Time: |
72 h |
| Result: |
Showed a broad spectrum of antitumor activity with the IC50s of 2.29, 2.85, 1.58, 1.16, 3.17, 2.41, 8.02, 2.62, 1.14, 0.60, 0.31, 0.39, 0.48, 0.51, 0.33, 0.38, 0.80, 0.47 µM for MDA-MB-231, A549, NCI-H460, HCT-116, SK-OV-3, HT-29, COLO 678, NCI-H441, 22Rv1, 786-O, TMD-8, DOHH-2, CCRF-CEM, SU-DHL-2, REC-1, MOLT-4, HUT-78, RS4;11 cells, respectively. |
Western Blot Analysis[1]
| Cell Line: |
TMD-8 cells |
| Concentration: |
2.5, 5, 7.5, 10 µM |
| Incubation Time: |
24 h |
| Result: |
Promoted the HDAC1, HDAC2, HDAC3 substrate Ace-H3 and Ace-H4 acetylation with a dose-dependent manner. |
Apoptosis Analysis[1]
| Cell Line: |
TMD-8 cells |
| Concentration: |
0.5, 1, 2, 4 µM |
| Incubation Time: |
24 h |
| Result: |
Induced cell apoptosis at a concentration-dependent manner. |
Cell Cycle Analysis[1]
| Cell Line: |
TMD-8 cells |
| Concentration: |
250, 500, 1000 nM |
| Incubation Time: |
24 h |
| Result: |
Arrested the cell cycle at G2/M phase in a dose-dependent manner. |
|
体内研究
(In Vivo) |
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[1].
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[1].
Pharmacokinetic Parameters of HDAC-IN-31 in mice[1].
| Parameters |
Unit |
24 g (25 mg/kg) |
| Cmax |
ng·h·mL-1 |
3100±231 |
| T1/2(po) |
h |
4.4±0.3 |
| AUC0-inf(iv) |
ng·h·mL-1 |
1040±142 |
| AUC0-inf(po) |
ng·h·mL-1 |
5180±252 |
| MRTPO |
h |
2.6±0.4 |
| F |
% |
39.9±2.1 |
ICR mouse; 2 mg/kg for i.v.; 25 mg/kg for p.o.[1].
Pharmacokinetic Parameters of HDAC-IN-31 in tumor models[1].
| Parameters |
Unit |
po (25 mg/kg) |
po (50 mg/kg) |
po (100 mg/kg) |
| Cmax |
ng·h·mL-1 |
1700±317 |
14700±1024 |
10700±1001 |
| AUC0-t |
ng·h·mL-1 |
1220±242 |
9710±314 |
9740±230 |
| AUC0-inf |
ng·h·mL-1 |
1230±165 |
9730±341 |
9770±332 |
| MRT0-t |
h |
0.750±0.043 |
0.812±0.023 |
1.43±0.56 |
| MRT0-inf |
h |
0.805±0.086 |
0.821±0.041 |
1.51±0.32 |
Mouse; 25, 50, 100 mg/kg for p.o.[1].
Pharmacokinetic Parameters of HDAC-IN-31 in tumor models[1].
| PK parameters |
Unit |
iv (2 mg/kg) |
po (10 mg/kg) |
po (100 mg/kg) |
| Cmax |
ng·h·mL-1 |
|
3960±413 |
58300±1352 |
| T1/2 |
h |
0.427±0.016 |
1.31±0.27 |
1.63±0.52 |
| AUC0-inf |
ng·h·mL-1 |
1250±132 |
2670±286 |
57200±1047 |
| MRT |
h |
0.402±0.032 |
0.919±0.052 |
0.897±0.041 |
| CL |
mL·kg·min-1 |
27.2±1.2 |
|
|
| F |
% |
|
45.6±1.2 |
91.8±2.3 |
ICR mice; 2 mg/kg for i.v.; 10, 100 mg/kg for p.o.[1].
Pharmacokinetic Parameters of HDAC-IN-31 in tumor models[1].
| PK parameters |
Unit |
Monkey |
Dog |
|
|
iv (1 mg/kg) |
po (10 mg/kg) |
iv (1 mg/kg) |
po (10 mg/kg) |
| Cmax |
ng·h·mL-1 |
|
8520±301 |
|
4740±243 |
| T1/2 |
h |
4.31±0.56 |
9.14±0.32 |
1.65±0.41 |
1.51±0.33 |
| AUC0-inf |
ng·h·mL-1 |
15700±1842 |
53200±1241 |
2550±365 |
15100±2004 |
| MRT |
h |
3.41±0.12 |
8.28±0.32 |
2.26±0.41 |
2.71±0.32 |
| CL |
mL·kg·min-1 |
1.35±0.21 |
|
6.72±0.35 |
|
| Vdss |
L·kg-1 |
0.34±0.22 |
|
0.55±0.04 |
|
| F |
% |
|
27.6±2.1 |
|
58.9±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[1].
Shanghai Jinpan Biotech Co Ltd has not independently confirmed the accuracy of these methods. They are for reference only.
| Animal Model: |
ICR mice[1] |
| 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[1] |
| Dosage: |
25, 50, 100 mg/kg |
| Administration: |
P.o. |
| Result: |
Did not exhibit a significant dose dependent for oral administration. |
| Animal Model: |
ICR mice[1] |
| 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[1] |
| 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)[1] |
| 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. |
|
