FRET assay for live-cell high-throughput screening of the cardiac SERCA pump yields multiple classes of small-molecule allosteric modulators
Roopnarine, O.; Yuen, S. L.; Thompson, A. R.; Roelike, L. N.; Rebbeck, R. T.; Bidwell, P. A.; Aldrich, C. C.; Cornea, R. L.; Thomas, D. D.
Show abstract
We have used FRET-based biosensors in live cells, in a robust high-throughput screening (HTS) platform, to identify small-molecules that alter the structure and activity of the cardiac sarco/endoplasmic reticulum calcium ATPase (SERCA2a). Our primary aim is to discover drug-like small-molecule activators that improve SERCAs function for the treatment of heart failure. We have previously demonstrated the use of an intramolecular FRET biosensor, based on human SERCA2a, by screening a small validation library using novel microplate readers that can detect the fluorescence lifetime or emission spectrum with high speed, precision, and resolution. Here we report results from a 50,000-compound screen using the same biosensor, with hit compounds functionally evaluated using Ca2+-ATPase and Ca2+-transport assays. We focused on 18 hit compounds, from which we identified eight structurally unique compounds and four compound classes as SERCA modulators, approximately half of which are activators and half are inhibitors. While both activators and inhibitors have therapeutic potential, the activators establish the basis for future testing in heart disease models and lead development, toward pharmaceutical therapy for heart failure.
Matching journals
The top 9 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- From atoms to cells: bridging the gap between potency, efficacy, and safety of small molecules directed at a membrane protein 96%
- PKIS Deep Dive Yields a Chemical Starting Point for Dark Kinases and a Cell Active BRSK2 Inhibitor 95%
- Structure-activity relationship studies of three novel 4-aminopyridine K+ channel blockers 95%
Similar papers in this journal
- Repurposing of the RIPK1 selective benzooxazepin-4-one scaffold for the development of a type-III LIMK1/2 inhibitor 95%
- Small Molecule Activation of NAPE-PLD Enhances Efferocytosis by Macrophages 95%
- Rational development of a small-molecule activator of CK1γ2 that decreases C99 and beta-amyloid levels 94%
Similar papers in this journal
- Stereo-specific Lasofoxifene Derivatives Reveal the Interplay between Estrogen Receptor Alpha Stability and Antagonistic Activity in ESR1 Mutant Breast Cancer Cells 93%
- An unconventional gatekeeper mutation sensitizes inositol hexakisphosphate kinases to an allosteric inhibitor 93%
- Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology 93%
Similar papers in this journal
- Drug repurposing screens identifies compounds that inhibit α-synuclein oligomers' membrane disruption and block antibody interactions 94%
- Discovery of cell active macrocyclic peptides with on-target inhibition of KRAS signaling 93%
- Transfer learning enables discovery of sub-micromolar antibacterials for ESKAPE pathogens from ultra-large chemical spaces 92%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.