title: 4-Pyridylanilinothiazoles that selectively target von Hippel-Lindau deficient renal cell carcinoma cells by inducing autophagic cell death.
abstract: 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 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.
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand. m.hay@auckland.ac.nz
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hay
authors.forename: Sandra
authors.initials: S
authors.lastname: Turcotte
authors.forename: Jack U
authors.initials: JU
authors.lastname: Flanagan
authors.forename: Muriel
authors.initials: M
authors.lastname: Bonnet
authors.forename: Denise A
authors.initials: DA
authors.lastname: Chan
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Sutphin
authors.forename: Phuong
authors.initials: P
authors.lastname: Nguyen
authors.forename: Amato J
authors.initials: AJ
authors.lastname: Giaccia
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D006801:Humans; D008247:Lysosomes / Q000187:drug effects; D011725:Pyridines; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006623:von Hippel-Lindau Disease / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000814:Aniline Compounds; D011725:Pyridines; D013844:Thiazoles; C023666:pyridine