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Start Over Author "John Xue" Journal acs medicinal chemistry letters
2 results on '"John Xue"'

1. Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-XL Inhibitor

Author

Paul Nimmer, Erwin R. Boghaert, Robin R. Frey, Phuong N Le, Andrew J. Souers, Peter Kovar, Wenqing Gao, Deepak Sampath, Dolores Diaz, Haichao Zhang, T. Matthew Hansen, Michael J. Mitten, Stephen K. Tahir, Russell A. Judge, Edna F. Choo, Yu Xiao, Shashank Shekhar, Xiaohong Song, George Doherty, Zhi-Fu Tao, Andrew S. Judd, Wayne J. Fairbrother, Michael D. Wendt, Steven W. Elmore, Kunzer Aaron R, Le Wang, Xilu Wang, Darren C. Phillips, Morey L. Smith, John A. Flygare, John Xue, Joel D. Leverson, Milan Bruncko, Chang H. Park, and Nathaniel D. Catron

Subjects
Drug, media_common.quotation_subject, A-1331852, Design elements and principles, BCL-2, Bcl-xL, Pharmacology, 01 natural sciences, Biochemistry, BCL-XL, Drug Discovery, media_common, biology, 010405 organic chemistry, Drug discovery, Chemistry, Organic Chemistry, apoptosis, A-1155463, Featured Letter, 0104 chemical sciences, Bioavailability, 010404 medicinal & biomolecular chemistry, Orally active, structure-based drug design (SBDD), Apoptosis, biology.protein, Pharmacophore
Abstract

Herein we describe the discovery of A-1331852, a first-in-class orally active BCL-XL inhibitor that selectively and potently induces apoptosis in BCL-XL-dependent tumor cells. This molecule was generated by re-engineering our previously reported BCL-XL inhibitor A-1155463 using structure-based drug design. Key design elements included rigidification of the A-1155463 pharmacophore and introduction of sp3-rich moieties capable of generating highly productive interactions within the key P4 pocket of BCL-XL. A-1331852 has since been used as a critical tool molecule for further exploring BCL-2 family protein biology, while also representing an attractive entry into a drug discovery program.

Published
2020

2. Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity

Author

Russell A. Judge, Sha Jin, Lisa A. Hasvold, Andrew J. Souers, Guillaume Lessene, John Xue, Hans E. Purkey, Jun Chen, Chang H. Park, Sarah G. Hymowitz, Nathaniel D. Catron, Xilu Wang, Le Wang, Wayne J. Fairbrother, Brian J. Smith, Brad E. Sleebs, Erwin R. Boghaert, Kurt Deshayes, Chudi Ndubaku, Yu Xiao, Darren C. Phillips, Stephen K. Tahir, Steven W. Elmore, Michael J. Mitten, Zhi-Fu Tao, Keith G. Watson, Michael F. T. Koehler, Anatol Oleksijew, Saul H. Rosenberg, Peter Kovar, Paul Nimmer, Andrew M. Petros, Chris Tse, Morey L. Smith, Peter M. Colman, Haichao Zhang, Kerry Zobel, Joel D. Leverson, Peter E. Czabotar, and John A. Flygare

Subjects
Navitoclax, Apoptosis Inhibitor, biology, Organic Chemistry, Cancer, Bcl-xL, Pharmacology, medicine.disease, Multiple dosing, Biochemistry, chemistry.chemical_compound, chemistry, Cell culture, Apoptosis, In vivo, Drug Discovery, biology.protein, medicine
Abstract

A-1155463, a highly potent and selective BCL-XL inhibitor, was discovered through nuclear magnetic resonance (NMR) fragment screening and structure-based design. This compound is substantially more potent against BCL-XL-dependent cell lines relative to our recently reported inhibitor, WEHI-539, while possessing none of its inherent pharmaceutical liabilities. A-1155463 caused a mechanism-based and reversible thrombocytopenia in mice and inhibited H146 small cell lung cancer xenograft tumor growth in vivo following multiple doses. A-1155463 thus represents an excellent tool molecule for studying BCL-XL biology as well as a productive lead structure for further optimization.

Published
2014
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