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Discovery of a potent Gilteritinib-based FLT3-PROTAC degrader for the treatment of Acute myeloid leukemia.
- Source :
-
Bioorganic chemistry [Bioorg Chem] 2024 Aug; Vol. 149, pp. 107477. Date of Electronic Publication: 2024 May 19. - Publication Year :
- 2024
-
Abstract
- Fms-like tyrosine receptor kinase 3 (FLT3) proteolysis targeting chimeras (PROTACs) emerge as a promising approach to overcome the limitations of FLT3 inhibitors, while the development of orally bioavailable FLT3-PROTACs faces great challenges. Here, we report the rational design and evaluation of a series of Gilteritinib-based FLT3-PROTACs. Among them, B3-2 exhibited the strongest antiproliferative activity against FLT3-ITD mutant AML cells, and significantly induced FLT3-ITD protein degradation. Mechanistic investigations demonstrated that B3-2 induced FLT3-ITD degradation in a ubiquitin-proteasome-dependent manner. More importantly, B3-2 exhibited an oral bioavailability of 5.65%, and oral administration of B3-2 showed good antitumor activity in MV-4-11 xenograft models. Furthermore, B3-2 showed strong antiproliferative activity against FLT3 resistant mutations, highlighting its potential in overcoming drug resistance.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Animals
Structure-Activity Relationship
Molecular Structure
Mice
Drug Discovery
Thiophenes chemistry
Thiophenes pharmacology
Thiophenes chemical synthesis
Proteolysis drug effects
Aniline Compounds chemistry
Aniline Compounds pharmacology
Aniline Compounds chemical synthesis
Cell Line, Tumor
Neoplasms, Experimental drug therapy
Neoplasms, Experimental pathology
Neoplasms, Experimental metabolism
fms-Like Tyrosine Kinase 3 antagonists & inhibitors
fms-Like Tyrosine Kinase 3 metabolism
Leukemia, Myeloid, Acute drug therapy
Leukemia, Myeloid, Acute pathology
Antineoplastic Agents pharmacology
Antineoplastic Agents chemistry
Antineoplastic Agents chemical synthesis
Pyrazines chemistry
Pyrazines pharmacology
Pyrazines chemical synthesis
Cell Proliferation drug effects
Protein Kinase Inhibitors pharmacology
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors chemical synthesis
Drug Screening Assays, Antitumor
Dose-Response Relationship, Drug
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2120
- Volume :
- 149
- Database :
- MEDLINE
- Journal :
- Bioorganic chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38820938
- Full Text :
- https://doi.org/10.1016/j.bioorg.2024.107477