Discovery of novel 4-azaaryl-N-phenylpyrimidin-2-amine derivatives as potent and selective FLT3 inhibitors for acute myeloid leukaemia with FLT3 mutations
| Autor: | Jasmine D. Karanjia, Lianmeng Kou, Alemwork A. Kebede, Yi Long, Sunita K.C. Basnet, Aleksandra M. Ochnik, Mingfeng Yu, Shudong Wang |
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| Přispěvatelé: | Long, Yi, Yu, Mingfeng, Ochnik, Aleksandra M, Karanjia, Jasmine D, KC Basnet, Sunita, Kebede, Alemwork A, Kou, Lianmeng, Wang, Shudong |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Gene isoform
FLT3-ITD Cell Survival Mutant Antineoplastic Agents 01 natural sciences 03 medical and health sciences Structure-Activity Relationship fluids and secretions AML hemic and lymphatic diseases Gene duplication Drug Discovery Tumor Cells Cultured Humans Amines FLT3 inhibitor Protein Kinase Inhibitors anti-AML drug discovery 030304 developmental biology Cell Proliferation Pharmacology FLT3-D835Y 0303 health sciences Aza Compounds Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Effector Kinase Organic Chemistry hemic and immune systems General Medicine 0104 chemical sciences Leukemia Myeloid Acute Pyrimidines fms-Like Tyrosine Kinase 3 Cell culture embryonic structures Cancer research Phosphorylation Drug Screening Assays Antitumor FLT3 Inhibitor |
| Popis: | Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3) is one of the most pursued targets in the treatment of acute myeloid leukaemia (AML) as its gene amplification and mutations, particularly internal tandem duplication (ITD), contribute to the pathogenesis of AML and the resistance to known FLT3 inhibitors. To conquer this challenge, there is a quest for structurally novel FLT3 inhibitors. Herein, we report the discovery of a new series of 4-azaaryl-N-phenylpyrimidin-2-amine derivatives as potent and selective FLT3 inhibitors. Compounds 12b and 12r were capable of suppressing a wide range of mutated FLT3 kinases including ITD and D835Y mutants; the latter isoform is closely associated with acquired drug resistance. In addition, both compounds displayed an anti-proliferative specificity for FLT3-ITD-harbouring cell lines (i.e., MV4-11 and MOLM-13 cells) over those with expression of the wild-type kinase or even without FLT3 expression. In mechanistic studies using MV4-11 cells, 12b was found to diminish the phosphorylation of key downstream effectors of FLT3 and induce apoptosis, supporting an FLT3-ITD-targeted mechanism of its anti-proliferative action. Refereed/Peer-reviewed |
| Databáze: | OpenAIRE |
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