4-Pyridylanilinothiazoles That Selectively Target von Hippel-Lindau Deficient Renal Cell Carcinoma Cells by Inducing Autophagic Cell Death

被引：61

作者：

Hay, Michael P. ^{[1
]}

Turcotte, Sandra ^{[2
]}

Flanagan, Jack U. ^{[1
]}

Bonnet, Muriel ^{[1
]}

Chan, Denise A. ^{[2
]}

Sutphin, Patrick D. ^{[2
]}

Nguyen, Phuong ^{[2
]}

Giaccia, Amato J. ^{[2
]}

Denny, William A. ^{[1
]}

机构：

[1] Univ Auckland, Fac Med & Hlth Sci, Auckland Canc Soc Res Ctr, Auckland 1, New Zealand

[2] Stanford Univ, Sch Med, Dept Radiat Oncol, Stanford, CA 94305 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 02期

关键词：

TUMOR-SUPPRESSOR PROTEIN; GROWTH-FACTOR; GENE; CANCER; PVHL; RNA;

D O I：

10.1021/jm901457w

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 it 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 illustrates 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.

引用

页码：787 / 797

页数：11

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