Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening

Carl A. Machutta, Christopher S. Kollmann, Kenneth E. Lind, Xiaopeng Bai, Pan F. Chan, Jianzhong Huang, Lluis Ballell, Svetlana Belyanskaya, Gurdyal S. Besra, David Barros-Aguirre, Robert H. Bates, Paolo A. Centrella, Sandy S. Chang, Jing Chai, Anthony E. Choudhry, Aaron Coffin, Christopher P. Davie, Hongfeng Deng, Jianghe Deng, Yun Ding, Jason W. Dodson, David T. Fosbenner, Enoch N. Gao, Taylor L. Graham, Todd L. Graybill, Karen Ingraham, Walter P. Johnson, Bryan W. King, Christopher R. Kwiatkowski, Joël Lelièvre, Yue Li, Xiaorong Liu, Quinn Lu, Ruth Lehr, Alfonso Mendoza-Losana, John Martin, Lynn McCloskey, Patti McCormick, Heather P. O’Keefe, Thomas O’Keeffe, Christina Pao, Christopher B. Phelps, Hongwei Qi, Keith Rafferty, Genaro S. Scavello, Matt S. Steiginga, Flora S. Sundersingh, Sharon M. Sweitzer, Lawrence M. Szewczuk, Amy Taylor, May Fern Toh, Juan Wang, Minghui Wang, Devan J. Wilkins, Bing Xia, Gang Yao, Jean Zhang, Jingye Zhou, Christine P. Donahue, Jeffrey A. Messer, David Holmes, Christopher C. Arico-Muendel, Andrew J. Pope, Jeffrey W. Gross and Ghotas Evindar ()
Additional contact information
Carl A. Machutta: GlaxoSmithKline
Christopher S. Kollmann: GlaxoSmithKline
Kenneth E. Lind: GlaxoSmithKline
Xiaopeng Bai: GlaxoSmithKline
Pan F. Chan: GlaxoSmithKline
Jianzhong Huang: GlaxoSmithKline
Lluis Ballell: GlaxoSmithKline
Svetlana Belyanskaya: GlaxoSmithKline
Gurdyal S. Besra: University of Birmingham, School of Biosciences
David Barros-Aguirre: GlaxoSmithKline
Robert H. Bates: GlaxoSmithKline
Paolo A. Centrella: GlaxoSmithKline
Sandy S. Chang: GlaxoSmithKline
Jing Chai: GlaxoSmithKline
Anthony E. Choudhry: GlaxoSmithKline
Aaron Coffin: GlaxoSmithKline
Christopher P. Davie: GlaxoSmithKline
Hongfeng Deng: GlaxoSmithKline
Jianghe Deng: GlaxoSmithKline
Yun Ding: GlaxoSmithKline
Jason W. Dodson: GlaxoSmithKline
David T. Fosbenner: GlaxoSmithKline
Enoch N. Gao: GlaxoSmithKline
Taylor L. Graham: GlaxoSmithKline
Todd L. Graybill: GlaxoSmithKline
Karen Ingraham: GlaxoSmithKline
Walter P. Johnson: GlaxoSmithKline
Bryan W. King: GlaxoSmithKline
Christopher R. Kwiatkowski: GlaxoSmithKline
Joël Lelièvre: GlaxoSmithKline
Yue Li: GlaxoSmithKline
Xiaorong Liu: GlaxoSmithKline
Quinn Lu: GlaxoSmithKline
Ruth Lehr: GlaxoSmithKline
Alfonso Mendoza-Losana: GlaxoSmithKline
John Martin: GlaxoSmithKline
Lynn McCloskey: GlaxoSmithKline
Patti McCormick: GlaxoSmithKline
Heather P. O’Keefe: GlaxoSmithKline
Thomas O’Keeffe: GlaxoSmithKline
Christina Pao: GlaxoSmithKline
Christopher B. Phelps: GlaxoSmithKline
Hongwei Qi: GlaxoSmithKline
Keith Rafferty: GlaxoSmithKline
Genaro S. Scavello: GlaxoSmithKline
Matt S. Steiginga: GlaxoSmithKline
Flora S. Sundersingh: GlaxoSmithKline
Sharon M. Sweitzer: GlaxoSmithKline
Lawrence M. Szewczuk: GlaxoSmithKline
Amy Taylor: GlaxoSmithKline
May Fern Toh: GlaxoSmithKline
Juan Wang: GlaxoSmithKline
Minghui Wang: GlaxoSmithKline
Devan J. Wilkins: GlaxoSmithKline
Bing Xia: GlaxoSmithKline
Gang Yao: GlaxoSmithKline
Jean Zhang: GlaxoSmithKline
Jingye Zhou: GlaxoSmithKline
Christine P. Donahue: GlaxoSmithKline
Jeffrey A. Messer: GlaxoSmithKline
David Holmes: GlaxoSmithKline
Christopher C. Arico-Muendel: GlaxoSmithKline
Andrew J. Pope: GlaxoSmithKline
Jeffrey W. Gross: GlaxoSmithKline
Ghotas Evindar: GlaxoSmithKline

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery.

Date: 2017
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DOI: 10.1038/ncomms16081

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