Agouron Pharmaceuticals Inc. today reported that it hassuccessfully used "protein structure-based drug design" todevelop drugs to treat cancer and psoriasis.
The company's report today in the Journal of MedicinalChemistry is "the first case in the scientific literature ofanyone successfully designing chemically novel compoundsbased on the structure of the target," Peter Johnson, Agouron'spresident and chief executive officer, told BioWorld. "We thinkthis will be the landmark publication for a long time to come.
"This paper wipes away forever doubt about the technicalfeasibility of rational drug design," Johnson said.
A team of 30 Agouron scientists reported the atom-by-atomdesign of three drugs targeting the enzyme thymidylatesynthase.
TS is required for the proliferation of human tumor cells andpsoriatic skin cells. A commonly used anti-cancer drug, 5-fluorouracil (5-FU), inhibits TS activity. But toxicity hasinhibited its use.
Agouron scientists re-engineered 5-FU by removing a portionof the drug molecule responsible for kidney toxicity. However,the new molecule was 1,000 times less potent in inhibiting TS.Through cycles of design and analysis, guided by X-raycrystallography images of drug candidates interacting with TS,Agouron replaced the deleted portion of the original drug andsucceeded in re-establishing the potency against TS. In vitroexperiments showed the engineered compound killed humantumor cells and stopped proliferation of human skin cells.
Agouron also reported that it has designed two classes of TSinhibitors based on a functionally important portion of the TSenzyme. These new drugs insert themselves into the TS siteand jam its enzymatic activity.
The company, based in La Jolla, Calif., said it hopes to file itsfirst investigational new drug application by November forPhase I clinical trials for the topical treatment of psoriasis.
Agouron plans clinical trials in 1992 of two or possibly threeof its TS inhibitors against colon cancer and other humantumors.
Agouron stock (NASDAQ:AGPH) closed unchanged at $14 onTuesday.
-- Karen Bernstein BioWorld Staff
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