Overcoming myelosuppression due to synthetic lethal toxicity for FLT3-targeted acute myeloid leukemia therapy
Activating mutations in FLT3 confer poor prognosis for individuals with acute myeloid leukemia (AML). Clinically active investigational FLT3 inhibitors can achieve complete remissions but their utility has been hampered by acquired resistance and myelosuppression attributed to a ‘synthetic lethal to...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2014-12-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/03445 |
| _version_ | 1811236110622261248 |
|---|---|
| author | Alexander A Warkentin Michael S Lopez Elisabeth A Lasater Kimberly Lin Bai-Liang He Anskar YH Leung Catherine C Smith Neil P Shah Kevan M Shokat |
| author_facet | Alexander A Warkentin Michael S Lopez Elisabeth A Lasater Kimberly Lin Bai-Liang He Anskar YH Leung Catherine C Smith Neil P Shah Kevan M Shokat |
| author_sort | Alexander A Warkentin |
| collection | DOAJ |
| description | Activating mutations in FLT3 confer poor prognosis for individuals with acute myeloid leukemia (AML). Clinically active investigational FLT3 inhibitors can achieve complete remissions but their utility has been hampered by acquired resistance and myelosuppression attributed to a ‘synthetic lethal toxicity’ arising from simultaneous inhibition of FLT3 and KIT. We report a novel chemical strategy for selective FLT3 inhibition while avoiding KIT inhibition with the staurosporine analog, Star 27. Star 27 maintains potency against FLT3 in proliferation assays of FLT3-transformed cells compared with KIT-transformed cells, shows no toxicity towards normal human hematopoiesis at concentrations that inhibit primary FLT3-mutant AML blast growth, and is active against mutations that confer resistance to clinical inhibitors. As a more complete understanding of kinase networks emerges, it may be possible to define anti-targets such as KIT in the case of AML to allow improved kinase inhibitor design of clinical agents with enhanced efficacy and reduced toxicity. |
| first_indexed | 2024-04-12T12:03:17Z |
| format | Article |
| id | doaj.art-2fc4b7634483440a90814b4285cadf5e |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:03:17Z |
| publishDate | 2014-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-2fc4b7634483440a90814b4285cadf5e2022-12-22T03:33:47ZengeLife Sciences Publications LtdeLife2050-084X2014-12-01310.7554/eLife.03445Overcoming myelosuppression due to synthetic lethal toxicity for FLT3-targeted acute myeloid leukemia therapyAlexander A Warkentin0Michael S Lopez1Elisabeth A Lasater2Kimberly Lin3Bai-Liang He4Anskar YH Leung5Catherine C Smith6Neil P Shah7Kevan M Shokat8Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United StatesDepartment of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United StatesDivision of Hematology and Oncology, University of California, San Francisco, San Francisco, United StatesDivision of Hematology and Oncology, University of California, San Francisco, San Francisco, United StatesDivision of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong KongDivision of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong KongDivision of Hematology and Oncology, University of California, San Francisco, San Francisco, United StatesDivision of Hematology and Oncology, University of California, San Francisco, San Francisco, United StatesDepartment of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United StatesActivating mutations in FLT3 confer poor prognosis for individuals with acute myeloid leukemia (AML). Clinically active investigational FLT3 inhibitors can achieve complete remissions but their utility has been hampered by acquired resistance and myelosuppression attributed to a ‘synthetic lethal toxicity’ arising from simultaneous inhibition of FLT3 and KIT. We report a novel chemical strategy for selective FLT3 inhibition while avoiding KIT inhibition with the staurosporine analog, Star 27. Star 27 maintains potency against FLT3 in proliferation assays of FLT3-transformed cells compared with KIT-transformed cells, shows no toxicity towards normal human hematopoiesis at concentrations that inhibit primary FLT3-mutant AML blast growth, and is active against mutations that confer resistance to clinical inhibitors. As a more complete understanding of kinase networks emerges, it may be possible to define anti-targets such as KIT in the case of AML to allow improved kinase inhibitor design of clinical agents with enhanced efficacy and reduced toxicity.https://elifesciences.org/articles/03445staurosporineprotein kinaseleukemiaFLT3KITchemical synthesis |
| spellingShingle | Alexander A Warkentin Michael S Lopez Elisabeth A Lasater Kimberly Lin Bai-Liang He Anskar YH Leung Catherine C Smith Neil P Shah Kevan M Shokat Overcoming myelosuppression due to synthetic lethal toxicity for FLT3-targeted acute myeloid leukemia therapy eLife staurosporine protein kinase leukemia FLT3 KIT chemical synthesis |
| title | Overcoming myelosuppression due to synthetic lethal toxicity for FLT3-targeted acute myeloid leukemia therapy |
| title_full | Overcoming myelosuppression due to synthetic lethal toxicity for FLT3-targeted acute myeloid leukemia therapy |
| title_fullStr | Overcoming myelosuppression due to synthetic lethal toxicity for FLT3-targeted acute myeloid leukemia therapy |
| title_full_unstemmed | Overcoming myelosuppression due to synthetic lethal toxicity for FLT3-targeted acute myeloid leukemia therapy |
| title_short | Overcoming myelosuppression due to synthetic lethal toxicity for FLT3-targeted acute myeloid leukemia therapy |
| title_sort | overcoming myelosuppression due to synthetic lethal toxicity for flt3 targeted acute myeloid leukemia therapy |
| topic | staurosporine protein kinase leukemia FLT3 KIT chemical synthesis |
| url | https://elifesciences.org/articles/03445 |
| work_keys_str_mv | AT alexanderawarkentin overcomingmyelosuppressionduetosyntheticlethaltoxicityforflt3targetedacutemyeloidleukemiatherapy AT michaelslopez overcomingmyelosuppressionduetosyntheticlethaltoxicityforflt3targetedacutemyeloidleukemiatherapy AT elisabethalasater overcomingmyelosuppressionduetosyntheticlethaltoxicityforflt3targetedacutemyeloidleukemiatherapy AT kimberlylin overcomingmyelosuppressionduetosyntheticlethaltoxicityforflt3targetedacutemyeloidleukemiatherapy AT bailianghe overcomingmyelosuppressionduetosyntheticlethaltoxicityforflt3targetedacutemyeloidleukemiatherapy AT anskaryhleung overcomingmyelosuppressionduetosyntheticlethaltoxicityforflt3targetedacutemyeloidleukemiatherapy AT catherinecsmith overcomingmyelosuppressionduetosyntheticlethaltoxicityforflt3targetedacutemyeloidleukemiatherapy AT neilpshah overcomingmyelosuppressionduetosyntheticlethaltoxicityforflt3targetedacutemyeloidleukemiatherapy AT kevanmshokat overcomingmyelosuppressionduetosyntheticlethaltoxicityforflt3targetedacutemyeloidleukemiatherapy |