4-Pyridylanilinothiazoles that selectively target von Hippel-Lindau deficient renal cell carcinoma cells by inducing autophagic cell death.
4-Pyridylanilinothiazoles that selectively target von Hippel-Lindau deficient renal cell carcinoma cells by inducing autophagic cell death.
复制标题
DOI：
10.1021/jm901457w
复制
发表时间：
2010-01-28
影响因子：
7.3
通讯作者：
Denny, William A.
中科院分区：
文献类型：
--
作者：
Hay, Michael P.;Turcotte, Sandra;Flanagan, Jack U.;Bonnet, Muriel;Chan, Denise A.;Sutphin, Patrick D.;Nguyen, Phuong;Giaccia, Amato J.;Denny, William A.
肾细胞癌（RCC）对标准疗法是难治的，晚期RCC具有不良预后;因此晚期RCC的治疗代表未满足的临床需求。von Hippel-Lindau（VHL）肿瘤抑制基因在大多数RCC中突变或失活。我们最近发现了一个4-吡啶基-2-苯胺基噻唑（PAT）对VHL缺陷的肾细胞介导的诱导自噬和增加酸化的自溶体的选择性细胞毒性。我们报告探索结构活性关系（SAR）围绕这个PAT铅。在三个环中的每一个上具有取代基的类似物以及环之间的各种接头被合成，并使用配对的RCC 4细胞系在体外进行测试。描述不同化学特征对效力的相对空间贡献的等高线图说明了邻近吡啶环的具有进一步发展潜力的区域。探索这一领域的实例验证了这种方法，并可能为开发这种新的化学型作为治疗RCC的靶向方法提供机会。
Renal cell carcinomas (RCC) are refractory to standard therapy with advanced RCC having a poor prognosis; consequently treatment of advanced RCC represents an unmet clinical need. The von Hippel-Lindau (VHL) tumor suppressor gene is mutated or inactivated in a majority of RCCs. We recently identified a 4-pyridyl-2- anilinothiazole (PAT) with selective cytotoxicity against VHL-deficient renal cells mediated by induction of autophagy and increased acidification of autolysosomes. We report exploration of structure-activity relationships (SAR) around this PAT lead. Analogues with substituents on each of the three rings, and various linkers between rings, were synthesized and tested in vitro using paired RCC4 cell lines. A contour map describing the relative spatial contributions of different chemical features to potency illustrate a region, adjacent to the pyridyl ring, with potential for further development. Examples probing this domain validated this approach and may provide the opportunity to develop this novel chemotype as a targeted approach to the treatment of RCC.
登录
查看更多内容
影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
11.4
作者：
Na, X;Duan, HO;Wu, G
通讯作者：
Wu, G
DOI：
10.1073/pnas.93.20.10595
发表时间：
1996-10-01
影响因子：
11.1
作者：
Iliopoulos, O;Levy, AP;Goldberg, MA
通讯作者：
Goldberg, MA
影响因子：
45.3
作者：
Motzer, RJ;Mazumdar, M;Ferrara, J
通讯作者：
Ferrara, J
影响因子：
64.8
作者：
Maxwell, PH;Wiesener, MS;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ