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revised on 24.10.2018 and posted on 24.10.2018by Sara E. Kearney, Gergely Zahoránszky-Kőhalmi, Kyle R. Brimacombe, Mark J. Henderson, Caitlin Lynch, Tongan Zhao, Kanny K. Wan, Zina Itkin, Christopher Dillon, Min Shen, Dorian M. Cheff, Tobie D. Lee, Danielle Bougie, Ken Cheng, Nathan P. Coussens, Dorjbal Dorjsuren, Richard T. Eastman, Ruili Huang, Michael J. Iannotti, Surendra Karavadhi, Carleen Klumpp-Thomas, Jacob S. Roth, Srilatha Sakamuru, Wei Sun, Steven A. Titus, Adam Yasgar, Ya-Qin Zhang, Jinghua Zhao, Rodrigo B. Andrade, M. Kevin Brown, Noah Z. Burns, Jin K. Cha, Emily E. Mevers, Jon Clardy, Jason A. Clement, Peter A. Crooks, Gregory D. Cuny, Jake Ganor, Jesus Moreno, Lucas
A. Morrill, Elias Picazo, Robert B. Susick, Neil K. Garg, Brian C. Goess, Robert B. Grossman, Chambers
C. Hughes, Jeffrey N. Johnston, Madeleine M. Joullié, A. Douglas Kinghorn, David G.I. Kingston, Michael J. Krische, Ohyun Kwon, Thomas J. Maimone, Susruta Majumdar, Katherine N. Maloney, Enas Mohamed, Brian T. Murphy, Pavel Nagorny, David E. Olson, Larry E. Overman, Lauren E. Brown, John K. Snyder, John A. Porco, Jr., Fatima Rivas, Samir A. Ross, Richmond Sarpong, Indrajeet Sharma, Jared T. Shaw, Zhengren Xu, Ben Shen, Wei Shi, Corey Stephenson, Alyssa L. Verano, Derek S. Tan, Yi Tang, Richard E. Taylor, Regan J. Thomson, David A. Vosburg, Jimmy Wu, William M. Wuest, Armen Zakarian, Yufeng Zhang, Tianjing Ren, Zhong Zuo, James Inglese, Sam Michael, Anton Simeonov, Wei Zheng, Paul Shinn, Ajit Jadhav, Matthew B. Boxer, Matthew D. Hall, Menghang Xia, Rajarshi Guha, Jason M. Rohde
Natural products and
their derivatives continue to be wellsprings of nascent therapeutic potential.
However, many laboratories have limited resources for biological evaluation, leaving
their previously isolated or synthesized compounds largely or completely untested.
To address this issue, the Canvass library of natural products was assembled,
in collaboration with academic and industry researchers, for quantitative high-throughput
screening (qHTS) across a diverse set of cell-based and biochemical assays. Characterization
of the library in terms of physicochemical properties, structural diversity,
and similarity to compounds in publicly available libraries indicates that the
Canvass library contains many structural elements in common with approved drugs.
The assay data generated were analyzed using a variety of quality control
metrics, and the resultant assay profiles were explored using statistical
methods, such as clustering and compound promiscuity analyses. Individual
compounds were then sorted by structural class and activity profiles. Differential
behavior based on these classifications, as well as noteworthy activities, are
outlined herein. One such highlight is the activity of (–)-2(S)-cathafoline,
which was found to stabilize calcium levels in the endoplasmic reticulum. The
workflow described here illustrates a pilot effort to broadly survey the
biological potential of natural products by utilizing the power of automation
and high-throughput screening.