Novel pyrrolidine diketopiperazines selectively inhibit melanoma cells via induction of late-onset apoptosis.
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.
Torrey Pines Institute for Molecular Studies , 11350 South West Village Parkway, Port St. Lucie, Florida 34987, United States.
Lillian
L
Onwuha-Ekpete
Lisa
L
Tack
Anna
A
Knapinska
Lyndsay
L
Smith
Gaurav
G
Kaushik
Travis
T
Lavoi
Marc
M
Giulianotti
Richard A
RA
Houghten
Gregg B
GB
Fields
Dmitriy
D
Minond
D000818:Animals; D017209:Apoptosis; D008546:Melanoma, Experimental / Q000473:pathology*; D051379:Mice; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D011759:Pyrrolidines / Q000737:chemistry*
D010879:Piperazines; D011759:Pyrrolidines