一种基于akr1c3酶的新型靶向抗癌药物ast-106.ppt

AST-106与其它肿瘤 AKR1C3 在多种肿瘤细胞中高度表达 Guise et al., Cancer Res 2010 适应症 肝癌 前列腺癌 非小细胞肺癌 肾癌 胃癌 急性髓性白血病 慢性髓性白血病 急性淋巴性白血病 在19种恶性肿瘤中AKR1C3强阳性（6+）比例 (2700 样本) AKR1C3在肺癌细胞系中的表达及 AST-106活性 Compound ID Max Inhibition% RelIC50(μM) AbsIC50 (μM) AKR1C3 expression NCI-H460 103.7 0.0005 0.0006 ? NCI-H2228 85.8 0.0010 0.0023 ? NCI-H1651 99.5 0.0018 0.0019 ? HCC44 100.2 0.0021 0.0028 ? NCI-H2110 93.8 0.0035 0.0039 ? NCI-H2342 89.7 0.0065 0.0138 ? NCI-H1563 101.7 0.0131 0.0099 ? NCI-H1793 95.3 0.0133 0.0146 ? NCI-H28 92.5 0.0383 0.0468 ? NCI-H1435 81.8 0.1273 0.1770 ? NCI-H1869 86.2 0.2029 0.1801 ? NCI-H522 51.1 0.0042 1 ? NCI-HCC366 (slow growth) 25.7 1 1 ? NCI-H2052 (slow growth) 43.8 0.0838 #Intersect ?? NCI-H2347 84.1 0.0896 0.1159 ?? NCI-H2073 37.1 1 1 ?? HCC2444 22.2 1 1 ?? NCI-H2085 1.1 1 1 ?? NCI-H1155 50.7 0.9892 0.9053 ? NCI-H1838 5.9 1 1 ? 95D 31.3 1 1 ? HCC15 27.1 1 1 ? NCI-H23 6.5 1 1 ? NCI-H661 11.1 1 1 ? M 95-D HCC15 HCC 366 HCC44 NCI-H460 NCI-H661 NCI-H2052 NCI-H28 NCI-H1155 NCI-H2110 NCI-H1435 NCI-H1563 M Actin AKR1C3 M NCI-H1651 NCI-H1793 NCI-H1838 NCI-H1869 NCI-H2073 NCI-H2085 NCI-H2228 NCI-H23 NCI-H2342 NCI-H2347 NCI-H2444 NCI-H522 M Actin AKR1C3 TH2870在肺癌细胞系H460小鼠肿瘤移植模型中的药效 Time (days) Vehicle Docetaxel 10 mg/kg, iv, Q7DX3 (现有治疗药物） TH2870 1.5 mg/kg Q7DX3 TH2870, 5 mg/kg, Q7DX3 TH2870, 10 mg/kg, Q7DX3 GAPDH AKR1C3 35KD M Eca-109 T.T - 4 OE 21- 4 TE - 6 TE - 9 TE - 11 TE- 14 KYSE 410 TE - 4 TE – 8 TE - 15 COLO680N EC - G1 - 10 PC GAPDH AKR1C3 35KD M KYSE 70 KYSE 30 OE 33 - 4 KYSE 140 KYSE 150 KYSE 180 KYSE 270 KYSE 510 TE - 1 TE - 5 TE - 10 PC Cell lines Max Inhibition% AbsIC50 (μM) AKR1C3 TE-11 100.0 0.0027 ? TE-14 99.8 0.0047 ? OE 21 99.6 0.0052 ? T.T 93.7 0.0060 ? TE-6 96.7 0.0205 ? TE-9 100.0 0.0110 ? ECa-109 99.8 0.0174 ? KYSE 410 96.5 0.0108 ? TE-4 99.6 0.0099 ?- TE-8 88.3 0.0190 ?- TE-15 100.0 0.0029 ?- COLO680N 71.5 0.0662