Novel pyrrolidine diketopiperazines selectively inhibit melanoma cells via induction of late-onset apoptosis Article

Onwuha-Ekpete, L, Tack, L, Knapinska, A et al. (2014). Novel pyrrolidine diketopiperazines selectively inhibit melanoma cells via induction of late-onset apoptosis . JOURNAL OF MEDICINAL CHEMISTRY, 57(4), 1599-1608. 10.1021/jm4019542

cited authors

  • Onwuha-Ekpete, L; Tack, L; Knapinska, A; Smith, L; Kaushik, G; LaVoi, T; Giulianotti, M; Houghten, RA; Fields, GB; Minond, D

authors

abstract

  • A common liability of cancer drugs is toxicity to noncancerous cells. Thus, molecules are needed that are potent toward cancer cells while sparing healthy cells. The cost of traditional cell-based HTS is dictated by the library size, which is typically in the hundreds of thousands of individual compounds. Mixture-based combinatorial libraries offer a cost-effective alternative to single-compound libraries while eliminating the need for molecular target validation. Presently, lung cancer and melanoma cells were screened in parallel with healthy cells using a mixture-based library. A novel class of compounds was discovered that selectively inhibited melanoma cell growth via apoptosis with submicromolar potency while sparing healthy cells. Additionally, the cost of screening and biological follow-up experiments was significantly lower than in typical HTS. Our findings suggest that mixture-based phenotypic HTS can significantly reduce cost and hit-to-lead time while yielding novel compounds with promising pharmacology. © 2014 American Chemical Society.

publication date

  • February 27, 2014

published in

Digital Object Identifier (DOI)

start page

  • 1599

end page

  • 1608

volume

  • 57

issue

  • 4