Optimization of selective mitogen-activated protein kinase interacting kinases 1 and 2 inhibitors for the treatment of blast crisis leukemia
Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by bcr-abl1, a constitutively active tyrosine kinase fusion gene responsible for an abnormal proliferation of leukemic stem cells (LSCs). Inhibition of BCR-ABL1 kinase activity offers long-term relief to CML patients. However, for...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2020
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| Online Access: | https://hdl.handle.net/10356/139169 |
| _version_ | 1826118955676205056 |
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| author | Yang, Haiyan Chennamaneni, Lohitha Rao Ho, Melvyn Wai Tuck Ang, Shi Hua Tan, Eldwin Sum Wai Jeyaraj, Duraiswamy Athisayamani Yeap, Yoon Sheng Liu, Boping Ong, Esther H. Q. Joy, Joma Kanikadu Wee, John Liang Kuan Kwek, Perlyn Retna, Priya Dinie, Nurul Nguyen, Thuy Thi Hanh Tai, Shi Jing Manoharan, Vithya Pendharkar, Vishal Low, Choon Bing Chew, Yun Shan Vuddagiri, Susmitha Sangthongpitag, Kanda Choong, Meng Ling Lee, May Ann Kannan, Srinivasaraghavan Verma, Chandra Shekhar Poulsen, Anders Lim, Sharon Chuah, Charles Thuan Heng Ong, Tiong Sin Hill, Jeffrey Matter, Alex Nacro, Kassoum |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Yang, Haiyan Chennamaneni, Lohitha Rao Ho, Melvyn Wai Tuck Ang, Shi Hua Tan, Eldwin Sum Wai Jeyaraj, Duraiswamy Athisayamani Yeap, Yoon Sheng Liu, Boping Ong, Esther H. Q. Joy, Joma Kanikadu Wee, John Liang Kuan Kwek, Perlyn Retna, Priya Dinie, Nurul Nguyen, Thuy Thi Hanh Tai, Shi Jing Manoharan, Vithya Pendharkar, Vishal Low, Choon Bing Chew, Yun Shan Vuddagiri, Susmitha Sangthongpitag, Kanda Choong, Meng Ling Lee, May Ann Kannan, Srinivasaraghavan Verma, Chandra Shekhar Poulsen, Anders Lim, Sharon Chuah, Charles Thuan Heng Ong, Tiong Sin Hill, Jeffrey Matter, Alex Nacro, Kassoum |
| author_sort | Yang, Haiyan |
| collection | NTU |
| description | Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by bcr-abl1, a constitutively active tyrosine kinase fusion gene responsible for an abnormal proliferation of leukemic stem cells (LSCs). Inhibition of BCR-ABL1 kinase activity offers long-term relief to CML patients. However, for a proportion of them, BCR-ABL1 inhibition will become ineffective at treating the disease, and CML will progress to blast crisis (BC) CML with poor prognosis. BC-CML is often associated with excessive phosphorylated eukaryotic translation initiation factor 4E (eIF4E), which renders LSCs capable of proliferating via self-renewal, oblivious to BCR-ABL1 inhibition. In vivo, eIF4E is exclusively phosphorylated on Ser209 by MNK1/2. Consequently, a selective inhibitor of MNK1/2 should reduce the level of phosphorylated eIF4E and re-sensitize LSCs to BCR-ABL1 inhibition, thus hindering the proliferation of BC LSCs. We report herein the structure-activity relationships and pharmacokinetic properties of a selective MNK1/2 inhibitor clinical candidate, ETC-206, which in combination with dasatinib prevents BC-CML LSC self-renewal in vitro and enhances dasatinib antitumor activity in vivo. |
| first_indexed | 2024-10-01T04:52:02Z |
| format | Journal Article |
| id | ntu-10356/139169 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T04:52:02Z |
| publishDate | 2020 |
| record_format | dspace |
| spelling | ntu-10356/1391692020-05-18T00:39:09Z Optimization of selective mitogen-activated protein kinase interacting kinases 1 and 2 inhibitors for the treatment of blast crisis leukemia Yang, Haiyan Chennamaneni, Lohitha Rao Ho, Melvyn Wai Tuck Ang, Shi Hua Tan, Eldwin Sum Wai Jeyaraj, Duraiswamy Athisayamani Yeap, Yoon Sheng Liu, Boping Ong, Esther H. Q. Joy, Joma Kanikadu Wee, John Liang Kuan Kwek, Perlyn Retna, Priya Dinie, Nurul Nguyen, Thuy Thi Hanh Tai, Shi Jing Manoharan, Vithya Pendharkar, Vishal Low, Choon Bing Chew, Yun Shan Vuddagiri, Susmitha Sangthongpitag, Kanda Choong, Meng Ling Lee, May Ann Kannan, Srinivasaraghavan Verma, Chandra Shekhar Poulsen, Anders Lim, Sharon Chuah, Charles Thuan Heng Ong, Tiong Sin Hill, Jeffrey Matter, Alex Nacro, Kassoum School of Biological Sciences Science::Medicine Rodent Models Inhibitors Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by bcr-abl1, a constitutively active tyrosine kinase fusion gene responsible for an abnormal proliferation of leukemic stem cells (LSCs). Inhibition of BCR-ABL1 kinase activity offers long-term relief to CML patients. However, for a proportion of them, BCR-ABL1 inhibition will become ineffective at treating the disease, and CML will progress to blast crisis (BC) CML with poor prognosis. BC-CML is often associated with excessive phosphorylated eukaryotic translation initiation factor 4E (eIF4E), which renders LSCs capable of proliferating via self-renewal, oblivious to BCR-ABL1 inhibition. In vivo, eIF4E is exclusively phosphorylated on Ser209 by MNK1/2. Consequently, a selective inhibitor of MNK1/2 should reduce the level of phosphorylated eIF4E and re-sensitize LSCs to BCR-ABL1 inhibition, thus hindering the proliferation of BC LSCs. We report herein the structure-activity relationships and pharmacokinetic properties of a selective MNK1/2 inhibitor clinical candidate, ETC-206, which in combination with dasatinib prevents BC-CML LSC self-renewal in vitro and enhances dasatinib antitumor activity in vivo. ASTAR (Agency for Sci., Tech. and Research, S’pore) 2020-05-18T00:39:09Z 2020-05-18T00:39:09Z 2018 Journal Article Yang, H., Chennamaneni, L. R., Ho, M. W. T., Ang, S. H., Tan, E. S. W., Jeyaraj, D. A., . . . Nacro, K. (2018). Optimization of selective mitogen-activated protein kinase interacting kinases 1 and 2 inhibitors for the treatment of blast crisis leukemia. Journal of Medicinal Chemistry, 61(10), 4348-4369. doi:10.1021/acs.jmedchem.7b01714 0022-2623 https://hdl.handle.net/10356/139169 10.1021/acs.jmedchem.7b01714 29683667 2-s2.0-85046431610 10 61 4348 4369 en Journal of Medicinal Chemistry © 2018 American Chemical Society. All rights reserved. |
| spellingShingle | Science::Medicine Rodent Models Inhibitors Yang, Haiyan Chennamaneni, Lohitha Rao Ho, Melvyn Wai Tuck Ang, Shi Hua Tan, Eldwin Sum Wai Jeyaraj, Duraiswamy Athisayamani Yeap, Yoon Sheng Liu, Boping Ong, Esther H. Q. Joy, Joma Kanikadu Wee, John Liang Kuan Kwek, Perlyn Retna, Priya Dinie, Nurul Nguyen, Thuy Thi Hanh Tai, Shi Jing Manoharan, Vithya Pendharkar, Vishal Low, Choon Bing Chew, Yun Shan Vuddagiri, Susmitha Sangthongpitag, Kanda Choong, Meng Ling Lee, May Ann Kannan, Srinivasaraghavan Verma, Chandra Shekhar Poulsen, Anders Lim, Sharon Chuah, Charles Thuan Heng Ong, Tiong Sin Hill, Jeffrey Matter, Alex Nacro, Kassoum Optimization of selective mitogen-activated protein kinase interacting kinases 1 and 2 inhibitors for the treatment of blast crisis leukemia |
| title | Optimization of selective mitogen-activated protein kinase interacting kinases 1 and 2 inhibitors for the treatment of blast crisis leukemia |
| title_full | Optimization of selective mitogen-activated protein kinase interacting kinases 1 and 2 inhibitors for the treatment of blast crisis leukemia |
| title_fullStr | Optimization of selective mitogen-activated protein kinase interacting kinases 1 and 2 inhibitors for the treatment of blast crisis leukemia |
| title_full_unstemmed | Optimization of selective mitogen-activated protein kinase interacting kinases 1 and 2 inhibitors for the treatment of blast crisis leukemia |
| title_short | Optimization of selective mitogen-activated protein kinase interacting kinases 1 and 2 inhibitors for the treatment of blast crisis leukemia |
| title_sort | optimization of selective mitogen activated protein kinase interacting kinases 1 and 2 inhibitors for the treatment of blast crisis leukemia |
| topic | Science::Medicine Rodent Models Inhibitors |
| url | https://hdl.handle.net/10356/139169 |
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