A2AAR/HDAC-IN-1 (compound 14c) 是一种口服有效且平衡的
A2AAR/HDAC双抑制剂，其对 A
2AAR 的
Ki为 163.5 nM, 对
HDAC1的
IC50为 145.3 nM。A2AAR/HDAC-IN-1 具有抗癌 (
anticancer) 活性。
| 生物活性 |
A2AAR/HDAC-IN-1 (compound 14c) is an orally active, potent and balancedA2AAR/HDACdual inhibitor, with aKiof 163.5 nM for A2AAR and anIC50of 145.3 nM forHDAC1. A2AAR/HDAC-IN-1 showsanticanceractivity[1].
|
| IC50& Target |
A2AR 163.5 ± 14 nM (Ki) |
A1AR 503.3 ± 14 nM (Ki) |
hA2B >10000 nM (Ki) |
Adenosine A3receptor >10000 nM (Ki) |
HDAC1 145.3 ± 12 nM (IC50) |
HDAC2 240.2 ± 19 nM (IC50) |
HDAC3 443.5 ± 27 nM (IC50) |
HDAC6 >10000 nM (IC50) |
HDAC8 >10000 nM (IC50) |
|
体外研究
(In Vitro) |
A2AAR/HDAC-IN-1 (compound 14c) (0-100 μM, 72 h) shows anti-proliferative activities against colon cancer cell lines, CT26 and MC38[1].
A2AAR/HDAC-IN-1 (0-5 μM, 24 h) increases histone acetylation[1].
A2AAR/HDAC-IN-1 shows moderate selectivity against A1AR (3-fold) and no significant binding for A2BAR and A3AR[1].
Cell Proliferation Assay[1]
| Cell Line: |
Colon cancer cell lines (CT26 and MC38) |
| Concentration: |
0-100 μM |
| Incubation Time: |
72 h |
| Result: |
Displayed good cytotoxicity in CT26 and MC38 cells, with GI50values of 0.29 ± 0.03 μM and 0.38 ± 0.03 μM, respectively. |
Western Blot Analysis[1]
| Cell Line: |
MC38 mouse colon cancer cells |
| Concentration: |
0, 0.1, 1, and 5 μM |
| Incubation Time: |
24 h |
| Result: |
Increased histone H3 and H4 acetylation in a concentration-dependent manner. |
|
体内研究
(In Vivo) |
A2AAR/HDAC-IN-1 (compound 14c) (30 or 60 mg/kg, IP, twice daily for 9 days) shows potent anti-tumor effects in the mouse MC38 xenograft model[1].
A2AAR/HDAC-IN-1 (90 mg/kg, bid; 150 mg/kg, qd; Oral gavage, for 15 days) shows weak tumor suppression[1].
A2AAR/HDAC-IN-1 (5 mg/kg, IV; 20 mg/kg PO or IP; once) shows an overall favorable pharmacokinetic profile[1].
| Animal Model: |
Male ICR mice (6-8 weeks, ~25 g body weight, MC38 colon cancer model)[1] |
| Dosage: |
30 or 60 mg/kg |
| Administration: |
IP, twice daily for 9 days |
| Result: |
Significantly inhibited tumor growth at a dosage of 30 mg/kg (ip, bid), with a tumor growth inhibition (TGI) rate of 68%. At a dosage of 60 mg/kg, the TGI rate was further increased to 85%. |
| Animal Model: |
Male ICR mice (6-8 weeks, ~25 g body weight, MC38 colon cancer model)[1] |
| Dosage: |
90 mg/kg, bid; 150 mg/kg, qd |
| Administration: |
Oral gavage, twice daily (90 mg/kg) or daily (150 mg/kg), for 15 days |
| Result: |
Showed only weak tumor suppression even at a dose of 90 mg/kg (po, bid), with inhibition rates of 44%. |
| Animal Model: |
Male ICR mice (6-8 weeks, ~25 g body weight)[1] |
| Dosage: |
5 mg/kg (IV) and 20 mg/kg (PO, IP) |
| Administration: |
Orally, IP, or IV; once (Pharmacokinetic Analysis) |
| Result: |
Pharmacokinetic Parameters of A2AAR/HDAC-IN-1 in male ICR mice[1].
| PK Parameters |
po (20 mg/kg) |
iv (5 mg/kg) |
ip (20 mg/kg) |
| Kel(h-1) |
0.390 ± 0.187 |
1.820 ± 0.300 |
0.844 ± 0.021 |
| t1/2(h) |
2.24 ± 1.16 |
0.389 ± 0.070 |
0.83 ± 0.02 |
| Tmax(h) |
0.333 ± 0.14 |
|
0.25 ± 0.00 |
| Cmax(ng/mL) |
3417 ± 1639 |
4703 ± 735 |
8411 ± 693 |
| C0(ng/mL) |
|
6498 ± 1285 |
|
| AUC0-t(ng/mL·h) |
3602 ± 1807 |
2098 ± 143 |
10022 ± 931 |
| CL (mL/min/kg) |
|
39.3 ± 2.3 |
33.5 ± 3.1 |
| 2767560-51-8 |
| 运输条件 |
Room temperature in continental US; may vary elsewhere.
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| 储存方式 |
Please store the product under the recommended conditions in the Certificate of Analysis.
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