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Connecting chemical structure to single cell signaling profiles
Hannah L Thirman1,2,3, Madeline J Grider-Hayes3, Laura C Geben1
1Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
Communications Biology
|July 31, 2025
Summary
Multiplexed activity profiling (MAP) helps study drug structure-activity relationships (SAR) in cells. This method identified a methoxy group on rocaglates responsible for anti-leukemia activity.
Area of Science:
- Chemical biology
- Molecular pharmacology
- Natural product chemistry
Background:
- Studying structure-activity relationships (SAR) in vivo within cells presents a significant challenge.
- Multiplexed activity profiling (MAP) is a high-throughput, single-cell technology suitable for natural product discovery and cellular function analysis.
Purpose of the Study:
- To apply SAR-MAP to systematically investigate the structural features responsible for the bioactivity of rocaglates.
- To identify specific structural variations driving anti-leukemia activity in cell lines and primary human cells.
Main Methods:
- Structure-activity relationship-multiplexed activity profiling (SAR-MAP) was employed to screen 600 rocaglate molecules.
- MV411 leukemia cells and healthy human leukocytes were used for proof-of-concept screening.
Main Results:
- Approximately half of the tested rocaglates (9 out of 19) were classified as bioactive.
- A methoxy substituent on rocaglate pyrimidinones was identified as crucial for anti-leukemia activity.
Conclusions:
- SAR-MAP is an effective approach for identifying structural determinants of natural product bioactivity.
- This method can prioritize molecules with specific cellular activities, such as anti-leukemia effects, for further research.
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