¹The Ronald O. Perelman Department of Dermatology and Department of Cell Biology, New York University School of Medicine, New York, New York, USA

Correspondence: Dr Seth J. Orlow, Department of Dermatology, Room H-100, NYU School of Medicine, 560 First Avenue, New York, New York 10016, USA. E-mail: seth.orlow@med.nyu.edu

Received 20 October 2006; Revised 6 March 2007; Accepted 7 March 2007.

Abstract

There is a continual need for compounds that effectively modulate melanin synthesis. To identify novel pigmentation modulators and their cellular targets, chemical genetic screenings were performed with triazine-based combinatorial libraries that include various linkers as intrinsic components of the small molecules in the library. The linker provides a ready means of attachment to beads, eliminating several common time-consuming downstream steps in the isolation of cellular targets for the small molecules of interest. Twelve compounds were identified as novel pigmentation modulators from various screenings performed in normal and albino murine melanocytes and zebrafish. Target identification by affinity chromatography revealed unexpected roles for prohibitin and mitochondrial F₁F₀-adenotriphosphatase in the regulation of mammalian pigmentation. The identification of prohibitin, a "scaffold protein", as a propigmentation effector represents a novel mechanism by which propigmentary signals are transduced. Results from our screenings provide potential active agents and targets for the medical and aesthetic treatment of disorders of pigmentation.