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Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia
Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we descri...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
Nature Publishing Group UK
2018
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| Materias: | |
| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297231/ https://www.ncbi.nlm.nih.gov/pubmed/30559424 http://dx.doi.org/10.1038/s41467-018-07551-w |
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| author | Tron, Adriana E. Belmonte, Matthew A. Adam, Ammar Aquila, Brian M. Boise, Lawrence H. Chiarparin, Elisabetta Cidado, Justin Embrey, Kevin J. Gangl, Eric Gibbons, Francis D. Gregory, Gareth P. Hargreaves, David Hendricks, J. Adam Johannes, Jeffrey W. Johnstone, Ricky W. Kazmirski, Steven L. Kettle, Jason G. Lamb, Michelle L. Matulis, Shannon M. Nooka, Ajay K. Packer, Martin J. Peng, Bo Rawlins, Philip B. Robbins, Daniel W. Schuller, Alwin G. Su, Nancy Yang, Wenzhan Ye, Qing Zheng, Xiaolan Secrist, J. Paul Clark, Edwin A. Wilson, David M. Fawell, Stephen E. Hird, Alexander W. |
| author_facet | Tron, Adriana E. Belmonte, Matthew A. Adam, Ammar Aquila, Brian M. Boise, Lawrence H. Chiarparin, Elisabetta Cidado, Justin Embrey, Kevin J. Gangl, Eric Gibbons, Francis D. Gregory, Gareth P. Hargreaves, David Hendricks, J. Adam Johannes, Jeffrey W. Johnstone, Ricky W. Kazmirski, Steven L. Kettle, Jason G. Lamb, Michelle L. Matulis, Shannon M. Nooka, Ajay K. Packer, Martin J. Peng, Bo Rawlins, Philip B. Robbins, Daniel W. Schuller, Alwin G. Su, Nancy Yang, Wenzhan Ye, Qing Zheng, Xiaolan Secrist, J. Paul Clark, Edwin A. Wilson, David M. Fawell, Stephen E. Hird, Alexander W. |
| author_sort | Tron, Adriana E. |
| collection | PubMed |
| description | Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD5991, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development. Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. Based on these promising data, a Phase I clinical trial has been launched for evaluation of AZD5991 in patients with hematological malignancies (NCT03218683). |
| format | Online Article Text |
| id | pubmed-6297231 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2018 |
| publisher | Nature Publishing Group UK |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-62972312018-12-19 Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia Tron, Adriana E. Belmonte, Matthew A. Adam, Ammar Aquila, Brian M. Boise, Lawrence H. Chiarparin, Elisabetta Cidado, Justin Embrey, Kevin J. Gangl, Eric Gibbons, Francis D. Gregory, Gareth P. Hargreaves, David Hendricks, J. Adam Johannes, Jeffrey W. Johnstone, Ricky W. Kazmirski, Steven L. Kettle, Jason G. Lamb, Michelle L. Matulis, Shannon M. Nooka, Ajay K. Packer, Martin J. Peng, Bo Rawlins, Philip B. Robbins, Daniel W. Schuller, Alwin G. Su, Nancy Yang, Wenzhan Ye, Qing Zheng, Xiaolan Secrist, J. Paul Clark, Edwin A. Wilson, David M. Fawell, Stephen E. Hird, Alexander W. Nat Commun Article Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD5991, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development. Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. Based on these promising data, a Phase I clinical trial has been launched for evaluation of AZD5991 in patients with hematological malignancies (NCT03218683). Nature Publishing Group UK 2018-12-17 /pmc/articles/PMC6297231/ /pubmed/30559424 http://dx.doi.org/10.1038/s41467-018-07551-w Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
| spellingShingle | Article Tron, Adriana E. Belmonte, Matthew A. Adam, Ammar Aquila, Brian M. Boise, Lawrence H. Chiarparin, Elisabetta Cidado, Justin Embrey, Kevin J. Gangl, Eric Gibbons, Francis D. Gregory, Gareth P. Hargreaves, David Hendricks, J. Adam Johannes, Jeffrey W. Johnstone, Ricky W. Kazmirski, Steven L. Kettle, Jason G. Lamb, Michelle L. Matulis, Shannon M. Nooka, Ajay K. Packer, Martin J. Peng, Bo Rawlins, Philip B. Robbins, Daniel W. Schuller, Alwin G. Su, Nancy Yang, Wenzhan Ye, Qing Zheng, Xiaolan Secrist, J. Paul Clark, Edwin A. Wilson, David M. Fawell, Stephen E. Hird, Alexander W. Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia |
| title | Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia |
| title_full | Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia |
| title_fullStr | Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia |
| title_full_unstemmed | Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia |
| title_short | Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia |
| title_sort | discovery of mcl-1-specific inhibitor azd5991 and preclinical activity in multiple myeloma and acute myeloid leukemia |
| topic | Article |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297231/ https://www.ncbi.nlm.nih.gov/pubmed/30559424 http://dx.doi.org/10.1038/s41467-018-07551-w |
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