Exploiting network biology to improve drug discovery.
Mammalian signal transduction occurs in the context of multiprotein complexes, yet currently available drug discovery strategies do not reflect this fact. We present a strategy for screening drugs and targets in living human cells by utilizing high content protein-fragment complementation assays. Synthetic fragments of a mutant fluorescent protein ("Venus" and/or enhanced yellow fluorescent protein) are used for protein-fragment complementation assay construction, allowing us to measure spatial and temporal changes in protein complexes in response to drugs that activate or inhibit particular pathways. Here we describe the utility of this novel strategy for high-throughput screening of known targets, and for screening previously undrugable targets and profiling drug leads for improved selectivity and safety.
MacDonald
Marnie L
ML
Odyssey Thera, Inc., San Ramon, CA, USA.
Westwick
John K
JK
D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D046912:Multiprotein Complexes / Q000378:metabolism*; D011485:Protein Binding; D034741:RNA, Small Interfering; D012680:Sensitivity and Specificity; D013347:Subcellular Fractions
D046912:Multiprotein Complexes; D034741:RNA, Small Interfering