Discovery of novel 4-azaaryl-N-phenylpyrimidin-2-amine derivatives as potent and selective FLT3 inhibitors for acute myeloid leukaemia with FLT3 mutations

Yi Long; Mingfeng Yu; Aleksandra M Ochnik; Jasmine D Karanjia; Sunita Kc Basnet; Alemwork A Kebede; Lianmeng Kou; Shudong Wang

doi:10.1016/j.ejmech.2021.113215

Discovery of novel 4-azaaryl-N-phenylpyrimidin-2-amine derivatives as potent and selective FLT3 inhibitors for acute myeloid leukaemia with FLT3 mutations

Eur J Med Chem. 2021 Mar 5:213:113215. doi: 10.1016/j.ejmech.2021.113215. Epub 2021 Jan 22.

Authors

Yi Long¹, Mingfeng Yu¹, Aleksandra M Ochnik¹, Jasmine D Karanjia¹, Sunita Kc Basnet¹, Alemwork A Kebede¹, Lianmeng Kou¹, Shudong Wang²

Affiliations

¹ Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5001, Australia.
² Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5001, Australia. Electronic address: shudong.wang@unisa.edu.au.

PMID: 33516985
DOI: 10.1016/j.ejmech.2021.113215

Abstract

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.

Keywords: AML; Anti-AML drug discovery; FLT3 inhibitor; FLT3-D835Y; FLT3-ITD.

MeSH terms

Amines / chemical synthesis
Amines / chemistry
Amines / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Aza Compounds / chemical synthesis
Aza Compounds / chemistry
Aza Compounds / pharmacology*
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Discovery
Drug Screening Assays, Antitumor
Humans
Leukemia, Myeloid, Acute / drug therapy*
Leukemia, Myeloid, Acute / metabolism
Leukemia, Myeloid, Acute / pathology
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship
Tumor Cells, Cultured
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
fms-Like Tyrosine Kinase 3 / metabolism

Substances

Amines
Antineoplastic Agents
Aza Compounds
Protein Kinase Inhibitors
Pyrimidines
FLT3 protein, human
fms-Like Tyrosine Kinase 3