The middle path
August 16, 2010 § Leave a comment
Drug discovery tends to happen via one of two main ways. Either you look for a phenotypic effect — as in, chewing that willow bark eased my headache, or this fungal extract stopped my rat liver membrane prep from making cholesterol — or you look for a specific effect on a purified target. Both have disadvantages [and advantages, of course]: an effect found in a phenotypic screen may be very hard to track down to a particular small molecule, and a specific mechanism, while a purified-target assay may give you many hits that don’t turn out to be useful in the complex environment of a whole cell, let alone the human body. Now Riki Eggert’s lab has shown that there is a middle path: targeting a whole pathway (Castoreno et al. 2010 Small molecules discovered in a pathway screen target the Rho pathway in cytokinesis. Nat Chem Biol. 6 457-63 PMID: 20436488).
Castoreno et al. were interested in finding inhibitors of the Rho pathway, a complex and many-branched pathway that is at the heart of several key cellular functions such as migration, adhesion, and cytokinesis, the process by which two daughter cells separate from each other once their DNA has doubled and divided. Rho itself is a GTPase that switches between two states, GTP-bound (active) and GDP-bound (inactive). Quite a few regulatory proteins are involved in this cycle, including the Guanine nucleotide Exchange Factors (GEFs), which encourage the exchange of bound GDP for GTP, and the GTPase Activating Proteins (GAPs), which encourage cleavage of the GTP to form GDP, inactivating Rho. Active Rho has several targets, and at least three of the pathways activated by Rho converge on cytokinesis.