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Discovery of a potent CDKs/FLT3 PROTAC with enhanced differentiation and proliferation inhibition for AML.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2024 Sep 05; Vol. 275, pp. 116539. Date of Electronic Publication: 2024 May 31. - Publication Year :
- 2024
-
Abstract
- AML is an aggressive malignancy of immature myeloid progenitor cells. Discovering effective treatments for AML through cell differentiation and anti-proliferation remains a significant challenge. Building on previous studies on CDK2 PROTACs with differentiation-inducing properties, this research aims to enhance CDKs degradation through structural optimization to facilitate the differentiation and inhibit the proliferation of AML cells. Compound C3, featuring a 4-methylpiperidine ring linker, effectively degraded CDK2 with a DC <subscript>50</subscript> value of 18.73 ± 10.78 nM, and stimulated 72.77 ± 3.51 % cell differentiation at 6.25 nM in HL-60 cells. Moreover, C3 exhibited potent anti-proliferative activity against various AML cell types. Degradation selectivity analysis indicated that C3 could be endowed with efficient degradation of CDK2/4/6/9 and FLT3, especially FLT3-ITD in MV4-11 cells. These findings propose that C3 combined targeting CDK2/4/6/9 and FLT3 with enhanced differentiation and proliferation inhibition, which holds promise as a potential treatment for AML.<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 Masson SAS. All rights reserved.)
- Subjects :
- Humans
Cell Differentiation drug effects
Cell Line, Tumor
Cell Proliferation drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Molecular Structure
Structure-Activity Relationship
Antineoplastic Agents pharmacology
Antineoplastic Agents chemistry
Antineoplastic Agents chemical synthesis
Cyclin-Dependent Kinases antagonists & inhibitors
Cyclin-Dependent Kinases metabolism
Drug Discovery
fms-Like Tyrosine Kinase 3 antagonists & inhibitors
fms-Like Tyrosine Kinase 3 metabolism
Leukemia, Myeloid, Acute drug therapy
Protein Kinase Inhibitors pharmacology
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors chemical synthesis
Proteolysis Targeting Chimera chemistry
Proteolysis Targeting Chimera pharmacology
Proteolysis Targeting Chimera therapeutic use
Proteolysis
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 275
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38878515
- Full Text :
- https://doi.org/10.1016/j.ejmech.2024.116539