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 A2AAR 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) |
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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. |
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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. | | 储存方式 | Please store the product under the recommended conditions in the Certificate of Analysis. |
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