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Rethinking mechanisms of drug discovery

A Roche team has concluded that overreliance on simplistic, target-centered screens early in drug development may inadvertently select for compounds destined to fail in late-stage trials.1 The resulting high attrition rates and low R&D productivity could be reversed, the researchers believe, by refocusing discovery strategies on phenotypic screens that account for complex mechanisms of action and cell signaling pathways.

"Late-stage drug failures involving, for example, poor bioavailability or off-target toxicity may ultimately derive from a preclinical optimization process that considered the target in an overly simplified setting-as typified, for example, by the classic in vitro binding assay, which doesn't enable optimization of the therapeutic index," corresponding author David Swinney told SciBX.

He suggests that, if they have not already done so, drug developers need to retool their preclinical programs to identify therapeutic candidates that have more subtle modes of action at their targets than simply high-affinity binding.

Swinney is cofounder, president and CEO of the not-for-profit Institute for Rare and Neglected Diseases Drug Discovery(iRND3). He previously was director of virology and biochemical pharmacology at Roche's unit in Palo Alto, Calif., before it closed in 2010 and consolidated with Roche R&D in Nutley, N.J.

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