Just a bit of self-promotion about my last papers. Drugs are usually classified as agonists or antagonists, however, little is known about how drugs modulate the activity of their intended target receptor over time. This is bizarre because the superiority of longitudinal vs cross-sectional studies is well accepted in clinical studies, so the temporal dynamics of drug action should be better explored in pre-clinical settings. Here, we used a longitudinal imaging approach to accurately follow the state of transcriptional activity of one drug target (the estrogen receptor) in 8 anatomical areas of living ERE-luc reporter mice over 21 consecutive days of treatment with 10 different Selective Estrogen Receptor Modulators (SERMs). Our results have important implications in term of estrogen therapy because we conclude that the study of the dynamics of receptor activity over time may facilitate the identification of SERMs able to mimic the physiological hormonal cycle.
During the study, we observed long-paced, noncircadian oscillation of ER transcriptional activity that is tissue-specific. Interestingly, each SERM caused tissue-specific perturbations on the ER transcriptional rythm which were predictive of the drug structure (after rational extraction of meaningful descriptors). Therefore, these studies also offer provocative perspectives into drug design, for instance we anticipate the possibility of a reverse approach in medicinal chemistry where the space-temporal plot of target activity drives the identification of subtle structure-activity relationships.
Rando, G., Horner, D., Biserni, A., Ramachandran, B., Caruso, D., Ciana, P., Komm, B., & Maggi, A. (2010). An Innovative Method to Classify SERMs Based on the Dynamics of Estrogen Receptor Transcriptional Activity in Living Animals Molecular Endocrinology, 24 (4), 735-744 DOI: 10.1210/me.2009-0514
Rando G, Biserni A, Ciana P, & Maggi A (2010). Profiling of drug action using reporter mice and molecular imaging. Methods in molecular biology (Clifton, N.J.), 602, 79-92 PMID: 20012393
Rando G, Arca S, Casiraghi E, Campadelli P & Maggi A (2009). Automatic Segmentation of Mouse Images. Proc 10th European Congress of International Society for Stereology, Bologna, Italy, 2009 link: abstract