title: Synergistic drug combinations tend to improve therapeutically relevant selectivity.
abstract: Drug combinations are a promising strategy to overcome the compensatory mechanisms and unwanted off-target effects that limit the utility of many potential drugs. However, enthusiasm for this approach is tempered by concerns that the therapeutic synergy of a combination will be accompanied by synergistic side effects. Using large scale simulations of bacterial metabolism and 94,110 multi-dose experiments relevant to diverse diseases, we provide evidence that synergistic drug combinations are generally more specific to particular cellular contexts than are single agent activities. We highlight six combinations whose selective synergy depends on multitarget drug activity. For one anti-inflammatory example, we show how such selectivity is achieved through differential expression of the drugs' targets in cell types associated with therapeutic, but not toxic, effects and validate its therapeutic relevance in a rat model of asthma. The context specificity of synergistic combinations creates many opportunities for therapeutically relevant selectivity and enables improved control of complex biological systems.
authors: CombinatoRx Inc., Cambridge, Massachusetts, USA.
authors: Joseph
authors: J
authors: Lehár
authors: Andrew S
authors: AS
authors: Krueger
authors: William
authors: W
authors: Avery
authors: Adrian M
authors: AM
authors: Heilbut
authors: Lisa M
authors: LM
authors: Johansen
authors: E Roydon
authors: ER
authors: Price
authors: Richard J
authors: RJ
authors: Rickles
authors: Glenn F
authors: GF
authors: Short
authors: Jane E
authors: JE
authors: Staunton
authors: Xiaowei
authors: X
authors: Jin
authors: Margaret S
authors: MS
authors: Lee
authors: Grant R
authors: GR
authors: Zimmermann
authors: Alexis A
authors: AA
authors: Borisy
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D055808:Drug Discovery; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D064420:Drug-Related Side Effects and Adverse Reactions; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D006801:Humans; D008297:Male; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D010600:Pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results
chemical_list: D004364:Pharmaceutical Preparations