Discovery of a Novel Orally Bioavailable FLT3-PROTAC Degrader for Efficient Treatment of Acute Myeloid Leukemia and Overcoming Resistance of FLT3 Inhibitors
Fms-like tyrosine receptor kinase 3 (FLT3) proteolysis-targeting chimeras (PROTACs) represent a promising approach to eliminate the resistance of FLT3 inhibitors. However, due to the poor druggability of PROTACs, the development of orally bioavailable FLT3-PROTACs faces great challenges. Herein, a novel orally bioavailable FLT3-ITD degrader A20 with excellent pharmacokinetic properties was discovered through reasonable design. A20 selectively inhibited the proliferation of FLT3-ITD mutant acute myeloid leukemia (AML) cells and potently induced FLT3-ITD degradation through the ubiquitin-proteasome system. Notably, oral administration of A20 resulted in complete tumor regression on subcutaneous AML xenograft models. Furthermore, on systemic AML xenograft models, A20 could completely eliminate the CD45+CD33+ human leukemic cells in murine and significantly prolonged the survival time of mice. Most importantly, A20 exerted significantly improved antiproliferative activity against drug-resistant AML cells compared to existing FLT3 inhibitors. These findings suggested that A20 could serve as a promising drug candidate for relapsed or refractory AML.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Journal of medicinal chemistry - (2024) vom: 24. Apr. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wang, Junwei [VerfasserIn] |
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Date Revised 24.04.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1021/acs.jmedchem.4c00051 |
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| PPN (Katalog-ID): |
NLM371445914 |
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| 100 | 1 | |a Wang, Junwei |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Discovery of a Novel Orally Bioavailable FLT3-PROTAC Degrader for Efficient Treatment of Acute Myeloid Leukemia and Overcoming Resistance of FLT3 Inhibitors |
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| 500 | |a Date Revised 24.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status Publisher | ||
| 520 | |a Fms-like tyrosine receptor kinase 3 (FLT3) proteolysis-targeting chimeras (PROTACs) represent a promising approach to eliminate the resistance of FLT3 inhibitors. However, due to the poor druggability of PROTACs, the development of orally bioavailable FLT3-PROTACs faces great challenges. Herein, a novel orally bioavailable FLT3-ITD degrader A20 with excellent pharmacokinetic properties was discovered through reasonable design. A20 selectively inhibited the proliferation of FLT3-ITD mutant acute myeloid leukemia (AML) cells and potently induced FLT3-ITD degradation through the ubiquitin-proteasome system. Notably, oral administration of A20 resulted in complete tumor regression on subcutaneous AML xenograft models. Furthermore, on systemic AML xenograft models, A20 could completely eliminate the CD45+CD33+ human leukemic cells in murine and significantly prolonged the survival time of mice. Most importantly, A20 exerted significantly improved antiproliferative activity against drug-resistant AML cells compared to existing FLT3 inhibitors. These findings suggested that A20 could serve as a promising drug candidate for relapsed or refractory AML | ||
| 650 | 4 | |a Journal Article | |
| 700 | 1 | |a Rong, Quanjin |e verfasserin |4 aut | |
| 700 | 1 | |a Ye, Lei |e verfasserin |4 aut | |
| 700 | 1 | |a Fang, Bingqian |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Yifan |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Haikun |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Dan |e verfasserin |4 aut | |
| 700 | 1 | |a He, Jinting |e verfasserin |4 aut | |
| 700 | 1 | |a Cui, Zhenzhen |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Qijian |e verfasserin |4 aut | |
| 700 | 1 | |a Kang, Di |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Lihong |e verfasserin |4 aut | |
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