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Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-X(L) Inhibitor
[Image: see text] Herein we describe the discovery of A-1331852, a first-in-class orally active BCL-X(L) inhibitor that selectively and potently induces apoptosis in BCL-X(L)-dependent tumor cells. This molecule was generated by re-engineering our previously reported BCL-X(L) inhibitor A-1155463 usi...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
American Chemical
Society
2020
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| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549103/ https://www.ncbi.nlm.nih.gov/pubmed/33062160 http://dx.doi.org/10.1021/acsmedchemlett.9b00568 |
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| author | Wang, Le Doherty, George A. Judd, Andrew S. Tao, Zhi-Fu Hansen, T. Matthew Frey, Robin R. Song, Xiaohong Bruncko, Milan Kunzer, Aaron R. Wang, Xilu Wendt, Michael D. Flygare, John A. Catron, Nathaniel D. Judge, Russell A. Park, Chang H. Shekhar, Shashank Phillips, Darren C. Nimmer, Paul Smith, Morey L. Tahir, Stephen K. Xiao, Yu Xue, John Zhang, Haichao Le, Phuong N. Mitten, Michael J. Boghaert, Erwin R. Gao, Wenqing Kovar, Peter Choo, Edna F. Diaz, Dolores Fairbrother, Wayne J. Elmore, Steven W. Sampath, Deepak Leverson, Joel D. Souers, Andrew James |
| author_facet | Wang, Le Doherty, George A. Judd, Andrew S. Tao, Zhi-Fu Hansen, T. Matthew Frey, Robin R. Song, Xiaohong Bruncko, Milan Kunzer, Aaron R. Wang, Xilu Wendt, Michael D. Flygare, John A. Catron, Nathaniel D. Judge, Russell A. Park, Chang H. Shekhar, Shashank Phillips, Darren C. Nimmer, Paul Smith, Morey L. Tahir, Stephen K. Xiao, Yu Xue, John Zhang, Haichao Le, Phuong N. Mitten, Michael J. Boghaert, Erwin R. Gao, Wenqing Kovar, Peter Choo, Edna F. Diaz, Dolores Fairbrother, Wayne J. Elmore, Steven W. Sampath, Deepak Leverson, Joel D. Souers, Andrew James |
| author_sort | Wang, Le |
| collection | PubMed |
| description | [Image: see text] Herein we describe the discovery of A-1331852, a first-in-class orally active BCL-X(L) inhibitor that selectively and potently induces apoptosis in BCL-X(L)-dependent tumor cells. This molecule was generated by re-engineering our previously reported BCL-X(L) inhibitor A-1155463 using structure-based drug design. Key design elements included rigidification of the A-1155463 pharmacophore and introduction of sp(3)-rich moieties capable of generating highly productive interactions within the key P4 pocket of BCL-X(L). 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. |
| format | Online Article Text |
| id | pubmed-7549103 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2020 |
| publisher | American Chemical
Society |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-75491032020-10-13 Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-X(L) Inhibitor Wang, Le Doherty, George A. Judd, Andrew S. Tao, Zhi-Fu Hansen, T. Matthew Frey, Robin R. Song, Xiaohong Bruncko, Milan Kunzer, Aaron R. Wang, Xilu Wendt, Michael D. Flygare, John A. Catron, Nathaniel D. Judge, Russell A. Park, Chang H. Shekhar, Shashank Phillips, Darren C. Nimmer, Paul Smith, Morey L. Tahir, Stephen K. Xiao, Yu Xue, John Zhang, Haichao Le, Phuong N. Mitten, Michael J. Boghaert, Erwin R. Gao, Wenqing Kovar, Peter Choo, Edna F. Diaz, Dolores Fairbrother, Wayne J. Elmore, Steven W. Sampath, Deepak Leverson, Joel D. Souers, Andrew James ACS Med Chem Lett [Image: see text] Herein we describe the discovery of A-1331852, a first-in-class orally active BCL-X(L) inhibitor that selectively and potently induces apoptosis in BCL-X(L)-dependent tumor cells. This molecule was generated by re-engineering our previously reported BCL-X(L) inhibitor A-1155463 using structure-based drug design. Key design elements included rigidification of the A-1155463 pharmacophore and introduction of sp(3)-rich moieties capable of generating highly productive interactions within the key P4 pocket of BCL-X(L). 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. American Chemical Society 2020-03-30 /pmc/articles/PMC7549103/ /pubmed/33062160 http://dx.doi.org/10.1021/acsmedchemlett.9b00568 Text en This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
| spellingShingle | Wang, Le Doherty, George A. Judd, Andrew S. Tao, Zhi-Fu Hansen, T. Matthew Frey, Robin R. Song, Xiaohong Bruncko, Milan Kunzer, Aaron R. Wang, Xilu Wendt, Michael D. Flygare, John A. Catron, Nathaniel D. Judge, Russell A. Park, Chang H. Shekhar, Shashank Phillips, Darren C. Nimmer, Paul Smith, Morey L. Tahir, Stephen K. Xiao, Yu Xue, John Zhang, Haichao Le, Phuong N. Mitten, Michael J. Boghaert, Erwin R. Gao, Wenqing Kovar, Peter Choo, Edna F. Diaz, Dolores Fairbrother, Wayne J. Elmore, Steven W. Sampath, Deepak Leverson, Joel D. Souers, Andrew James Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-X(L) Inhibitor |
| title | Discovery
of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable
BCL-X(L) Inhibitor |
| title_full | Discovery
of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable
BCL-X(L) Inhibitor |
| title_fullStr | Discovery
of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable
BCL-X(L) Inhibitor |
| title_full_unstemmed | Discovery
of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable
BCL-X(L) Inhibitor |
| title_short | Discovery
of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable
BCL-X(L) Inhibitor |
| title_sort | discovery
of a-1331852, a first-in-class, potent, and orally-bioavailable
bcl-x(l) inhibitor |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549103/ https://www.ncbi.nlm.nih.gov/pubmed/33062160 http://dx.doi.org/10.1021/acsmedchemlett.9b00568 |
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