A number of compounds have failed recently during clinical trials because of poorly predicted pharmacokinetics and toxicity related to being metabolized by aldehyde oxidase (AO). Not only do late-stage failures like these increase the cost and time to develop a drug, they also have a cost in human life. Since AO is an understudied enzyme we do not have the tools at our disposal to help develop AO substrates into drugs. The overarching goal of this work is to provide a basic understanding of how AO functions as a drug metabolizing enzyme to help drug discovery efforts. That this enzyme is of emerging importance is illustrated by the fact that 2 newly approved drugs over the past year are AO substrates. The following are the specific aims of this grant:
Specific Aims - 1.1) We hypothesize that in vitro inhibition models will provide predictive tools for drug/drug interaction associated with AO. Furthermore, we hypothesize that the model will help in understanding how to modulate substrate/inhibitor affinities for AO by establishing a pharmacophore for the enzyme. 1.2) We will use structure activity relationships (SAR) to explore the mechanism of AO. This is particularly important with respect to the continued development of computational predictive methods.
This Aim i s guided by the hypothesis that the ability to protonate a compound during catalysis is one of the key factors in determining if a drug will be an AO substrate. 1.3) The origins of the species differences for AO remain obscure and no good animal model is appropriate for allometric scaling for human clinical trials. We see significant differences in the kinetics even for very closely related species such as rhesus (rAO) and cynomolgus monkey (cAO). We hypothesize that we can understand the molecular basis for these differences by exploiting the amino acid differences between cAO and human (hAO) using site-directed mutagenesis and kinetics.
Aldehyde oxidase (AO) is an emerging drug metabolizing enzyme. Very little is known about AO, and humans have unique AO activity, so animal models are poor predictors of the fate of a potential drug in humans. A number of drugs have failed in phase I clinical trials, often putting the human subject in harms way. However, two newly approved drugs in the past year are AO substrates showing that we cannot just design away from this metabolic enzyme. The purpose of this grant is to elucidate the features of a molecule that make it an AO substrate, to develop predictive models for drug/drug interactions, and to understand how to choose preclinical species to accurately predict the human condition.
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