Divisions of Molecular Target and Gene Therapy Products, National Institute of Health Sciences , 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd. , 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-0012, Japan.
J Med Chem. 2018 Jan 25;61(2):543-575. doi: 10.1021/acs.jmedchem.7b00168. Epub 2017 Jun 23.
Targeted protein degradation using small molecules is a novel strategy for drug development. We have developed hybrid molecules named specific and nongenetic inhibitor of apoptosis protein [IAP]-dependent protein erasers (SNIPERs) that recruit IAP ubiquitin ligases to degrade target proteins. Here, we show novel SNIPERs capable of inducing proteasomal degradation of the androgen receptor (AR). Through derivatization of the SNIPER(AR) molecule at the AR ligand and IAP ligand and linker, we developed 42a (SNIPER(AR)-51), which shows effective protein knockdown activity against AR. Consistent with the degradation of the AR protein, 42a inhibits AR-mediated gene expression and proliferation of androgen-dependent prostate cancer cells. In addition, 42a efficiently induces caspase activation and apoptosis in prostate cancer cells, which was not observed in the cells treated with AR antagonists. These results suggest that SNIPER(AR)s could be leads for an anticancer drug against prostate cancers that exhibit AR-dependent proliferation.
利用小分子进行靶向蛋白降解是一种新的药物开发策略。我们开发了一种名为特异性和非遗传凋亡蛋白抑制物（IAP）依赖性蛋白清除剂（SNIPER）的混合分子，它可以招募 IAP 泛素连接酶来降解靶蛋白。在这里，我们展示了能够诱导雄激素受体（AR）蛋白水解的新型 SNIPER。通过在 AR 配体和 IAP 配体和连接子上对 SNIPER（AR）分子进行衍生化，我们开发了 42a（SNIPER（AR）-51），它对 AR 表现出有效的蛋白敲低活性。与 AR 蛋白的降解一致，42a 抑制 AR 介导的雄激素依赖性前列腺癌细胞的基因表达和增殖。此外，42a 能有效诱导前列腺癌细胞中 caspase 的激活和凋亡，而用 AR 拮抗剂处理的细胞则没有观察到这种现象。这些结果表明，SNIPER（AR）可能成为针对表现出 AR 依赖性增殖的前列腺癌的抗癌药物的先导。
