Causes and Significance of Increased Compound Potency in Cellular or Physiological Contexts

Abstract

Compound potency is a key metric that is often used to drive medicinal chemistry programs. Compound potency is also taken into account when identifying the mechanism of action of compounds whose pharmacological target is unknown, particularly when these compounds are identified in phenotypic screens. Often compound potency is determined from assays using recombinantly generated, purified protein. It is well understood in the medicinal chemistry community that potency measured with recombinant enzyme and potency measured in cell may not entirely coincide. Decreases in cellular vs recombinant potency are often anticipated or explainable. What is less often realized is that compound potency can increase in a cellular environment due to several factors including cellular metabolism of compounds, protein-protein interactions, post-translational modifications, and asymmetric intracellular localization of compound. Here we discuss these factors and highlight examples where increases in cellular compound potency were critical to the development of probes or drugs.

Pharmacophore-based design of novel 3-hydroxypyrimidine-2,4-dione subtypes as inhibitors of HIV reverse transcriptase-associated RNase H: Tolerance of a nonflexible linker

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“…Although comparisons between biochemical and cellular assays appear to be relatively straightforward, they are often hampered by shifts in potency across these model systems. − The reasons for these shifts are well-established and include factors that influence the intracellular availability of the compounds, i.e., serum protein binding, cell permeability and efflux, as well as competition for the intended binding sites with endogenous metabolites. The magnitude of these shifts naturally varies between compounds, thus complicating comparisons of structure–activity relationships.…”

Optimization of N-Substituted Oseltamivir Derivatives as Potent Inhibitors of Group-1 and -2 Influenza A Neuraminidases, Including a Drug-Resistant Variant

“…It is also noteworthy that 26b and 26c showed remarkably improved anti-H5N8 virus activity in the cellular system, although they displayed only moderate N8 (H5N8)-inhibitory activities. The phenomenon that the potency of compounds can increase in a cellular environment may be due to multiple factors, including synergistic inhibition,48 cellular metabolism, protein-protein interactions, and asymmetric intracellular localization 49.…”