ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets
Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of dir...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2013
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/107357 http://hdl.handle.net/10220/18024 http://dx.doi.org/10.1038/nm.3048 |
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| author | Hymowitz, Sarah G. Jin, Sha Khaw, Seong Lin Kovar, Peter J. Lam, Lloyd T. Lee, Jackie Maecker, Heather L. Marsh, Kennan C. Mason, Kylie D. Mitten, Michael J. Sampath, Deepak Nimmer, Paul M. Oleksijew, Anatol Park, Chang H. Park, Cheol-Min Phillips, Darren C. Roberts, Andrew W. Seymour, John F. Smith, Morey L. Sullivan, Gerard M. Tahir, Stephen K. Wendt, Michael D. Xiao, Yu Xue, John C. Zhang, Haichao Humerickhouse, Rod A. Rosenberg, Saul H. Elmore, Steven W. Tse, Chris Souers, Andrew J. Leverson, Joel D. Boghaert, Erwin R. Ackler, Scott L. Catron, Nathaniel D. Chen, Jun Dayton, Brian D. Ding, Hong Enschede, Sari H. Fairbrother, Wayne J. Huang, David C. S. |
| author2 | School of Physical and Mathematical Sciences |
| author_facet | School of Physical and Mathematical Sciences Hymowitz, Sarah G. Jin, Sha Khaw, Seong Lin Kovar, Peter J. Lam, Lloyd T. Lee, Jackie Maecker, Heather L. Marsh, Kennan C. Mason, Kylie D. Mitten, Michael J. Sampath, Deepak Nimmer, Paul M. Oleksijew, Anatol Park, Chang H. Park, Cheol-Min Phillips, Darren C. Roberts, Andrew W. Seymour, John F. Smith, Morey L. Sullivan, Gerard M. Tahir, Stephen K. Wendt, Michael D. Xiao, Yu Xue, John C. Zhang, Haichao Humerickhouse, Rod A. Rosenberg, Saul H. Elmore, Steven W. Tse, Chris Souers, Andrew J. Leverson, Joel D. Boghaert, Erwin R. Ackler, Scott L. Catron, Nathaniel D. Chen, Jun Dayton, Brian D. Ding, Hong Enschede, Sari H. Fairbrother, Wayne J. Huang, David C. S. |
| author_sort | Hymowitz, Sarah G. |
| collection | NTU |
| description | Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2–like 1 (BCL-XL), which has shown clinical efficacy in some BCL-2–dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-XL inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2–selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2–dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2–dependent hematological cancers. |
| first_indexed | 2024-10-01T03:57:25Z |
| format | Journal Article |
| id | ntu-10356/107357 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T03:57:25Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | ntu-10356/1073572019-12-06T22:29:15Z ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets Hymowitz, Sarah G. Jin, Sha Khaw, Seong Lin Kovar, Peter J. Lam, Lloyd T. Lee, Jackie Maecker, Heather L. Marsh, Kennan C. Mason, Kylie D. Mitten, Michael J. Sampath, Deepak Nimmer, Paul M. Oleksijew, Anatol Park, Chang H. Park, Cheol-Min Phillips, Darren C. Roberts, Andrew W. Seymour, John F. Smith, Morey L. Sullivan, Gerard M. Tahir, Stephen K. Wendt, Michael D. Xiao, Yu Xue, John C. Zhang, Haichao Humerickhouse, Rod A. Rosenberg, Saul H. Elmore, Steven W. Tse, Chris Souers, Andrew J. Leverson, Joel D. Boghaert, Erwin R. Ackler, Scott L. Catron, Nathaniel D. Chen, Jun Dayton, Brian D. Ding, Hong Enschede, Sari H. Fairbrother, Wayne J. Huang, David C. S. School of Physical and Mathematical Sciences DRNTU::Science::Chemistry::Biochemistry Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2–like 1 (BCL-XL), which has shown clinical efficacy in some BCL-2–dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-XL inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2–selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2–dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2–dependent hematological cancers. 2013-12-04T04:53:11Z 2019-12-06T22:29:15Z 2013-12-04T04:53:11Z 2019-12-06T22:29:15Z 2013 2013 Journal Article Souers, A. J., Leverson, J. D., Boghaert, E. R., Ackler, S. L., Catron, N. D., Chen, J., et al. (2013). ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nature medicine, 19(2), 202-208. https://hdl.handle.net/10356/107357 http://hdl.handle.net/10220/18024 http://dx.doi.org/10.1038/nm.3048 en Nature medicine |
| spellingShingle | DRNTU::Science::Chemistry::Biochemistry Hymowitz, Sarah G. Jin, Sha Khaw, Seong Lin Kovar, Peter J. Lam, Lloyd T. Lee, Jackie Maecker, Heather L. Marsh, Kennan C. Mason, Kylie D. Mitten, Michael J. Sampath, Deepak Nimmer, Paul M. Oleksijew, Anatol Park, Chang H. Park, Cheol-Min Phillips, Darren C. Roberts, Andrew W. Seymour, John F. Smith, Morey L. Sullivan, Gerard M. Tahir, Stephen K. Wendt, Michael D. Xiao, Yu Xue, John C. Zhang, Haichao Humerickhouse, Rod A. Rosenberg, Saul H. Elmore, Steven W. Tse, Chris Souers, Andrew J. Leverson, Joel D. Boghaert, Erwin R. Ackler, Scott L. Catron, Nathaniel D. Chen, Jun Dayton, Brian D. Ding, Hong Enschede, Sari H. Fairbrother, Wayne J. Huang, David C. S. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets |
| title | ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets |
| title_full | ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets |
| title_fullStr | ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets |
| title_full_unstemmed | ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets |
| title_short | ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets |
| title_sort | abt 199 a potent and selective bcl 2 inhibitor achieves antitumor activity while sparing platelets |
| topic | DRNTU::Science::Chemistry::Biochemistry |
| url | https://hdl.handle.net/10356/107357 http://hdl.handle.net/10220/18024 http://dx.doi.org/10.1038/nm.3048 |
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