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Design, synthesis and biological evaluation of 2-aminopyrimidine derivatives as potent FLT3 inhibitors. 2023

Xuanmin Lian, and Yue Gao, and Xuemei Li, and Peipei Wang, and Lexian Tong, and Jia Li, and Yubo Zhou, and Tao Liu
ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.

Acute myeloid leukemia (AML) is an aggressive cancer, which is characterized by clonal expansion of myeloid progenitors in the bone marrow and peripheral blood. FMS-like tyrosine kinase 3 (FLT3) mutations are the most frequently identified mutations, present in approximately 25-30 % AML patients, making FLT3 inhibitors a crucial treatment option for AML. In this study, we described the design, synthesis and biological evaluation of a series of 2-aminopyrimidine derivatives as potent FLT3 inhibitors. Notably, compound 15 displayed potent kinase inhibitory activities against FLT3 (FLT3-WT IC50 = 7.42 ± 1.23 nM; FLT3-D835Y IC50 = 9.21 ± 0.04 nM) and robust antiproliferative activities against MV4-11 cells (IC50 = 0.83 ± 0.15 nM) and MOLM-13 cells (IC50 = 10.55 ± 1.70 nM). Compound 15 also possessed potent antiproliferative activities against BaF3 cells carrying various FLT3-TKD and FLT3-ITD-TKD mutations, indicating its potential to overcome on-target resistance caused by FLT3 mutations. In summary, compound 15 showed promising potential for further exploration as a treatment of AML.

UI MeSH Term Description Entries
D009154 Mutation Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations. Mutations
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D015470 Leukemia, Myeloid, Acute Clonal expansion of myeloid blasts in bone marrow, blood, and other tissue. Myeloid leukemias develop from changes in cells that normally produce NEUTROPHILS; BASOPHILS; EOSINOPHILS; and MONOCYTES. Leukemia, Myelogenous, Acute,Leukemia, Nonlymphocytic, Acute,Myeloid Leukemia, Acute,Nonlymphocytic Leukemia, Acute,ANLL,Acute Myelogenous Leukemia,Acute Myeloid Leukemia,Acute Myeloid Leukemia with Maturation,Acute Myeloid Leukemia without Maturation,Leukemia, Acute Myelogenous,Leukemia, Acute Myeloid,Leukemia, Myeloblastic, Acute,Leukemia, Myelocytic, Acute,Leukemia, Myeloid, Acute, M1,Leukemia, Myeloid, Acute, M2,Leukemia, Nonlymphoblastic, Acute,Myeloblastic Leukemia, Acute,Myelocytic Leukemia, Acute,Myelogenous Leukemia, Acute,Myeloid Leukemia, Acute, M1,Myeloid Leukemia, Acute, M2,Nonlymphoblastic Leukemia, Acute,Acute Myeloblastic Leukemia,Acute Myeloblastic Leukemias,Acute Myelocytic Leukemia,Acute Myelocytic Leukemias,Acute Myelogenous Leukemias,Acute Myeloid Leukemias,Acute Nonlymphoblastic Leukemia,Acute Nonlymphoblastic Leukemias,Acute Nonlymphocytic Leukemia,Acute Nonlymphocytic Leukemias,Leukemia, Acute Myeloblastic,Leukemia, Acute Myelocytic,Leukemia, Acute Nonlymphoblastic,Leukemia, Acute Nonlymphocytic,Leukemias, Acute Myeloblastic,Leukemias, Acute Myelocytic,Leukemias, Acute Myelogenous,Leukemias, Acute Myeloid,Leukemias, Acute Nonlymphoblastic,Leukemias, Acute Nonlymphocytic,Myeloblastic Leukemias, Acute,Myelocytic Leukemias, Acute,Myelogenous Leukemias, Acute,Myeloid Leukemias, Acute,Nonlymphoblastic Leukemias, Acute,Nonlymphocytic Leukemias, Acute
D017209 Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, i.e., DNA FRAGMENTATION. It is genetically programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Apoptosis, Extrinsic Pathway,Apoptosis, Intrinsic Pathway,Caspase-Dependent Apoptosis,Classic Apoptosis,Classical Apoptosis,Programmed Cell Death,Programmed Cell Death, Type I,Apoptoses, Extrinsic Pathway,Apoptoses, Intrinsic Pathway,Apoptosis, Caspase-Dependent,Apoptosis, Classic,Apoptosis, Classical,Caspase Dependent Apoptosis,Cell Death, Programmed,Classic Apoptoses,Extrinsic Pathway Apoptoses,Extrinsic Pathway Apoptosis,Intrinsic Pathway Apoptoses,Intrinsic Pathway Apoptosis
D045744 Cell Line, Tumor A cell line derived from cultured tumor cells. Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines
D047428 Protein Kinase Inhibitors Agents that inhibit PROTEIN KINASES. Protein Kinase Inhibitor,Inhibitor, Protein Kinase,Inhibitors, Protein Kinase,Kinase Inhibitor, Protein,Kinase Inhibitors, Protein
D051941 fms-Like Tyrosine Kinase 3 A receptor tyrosine kinase that is involved in HEMATOPOIESIS. It is closely related to FMS PROTO-ONCOGENE PROTEIN and is commonly mutated in acute MYELOID LEUKEMIA. Antigens, CD135,CD135 Antigens,CD135 Antigen,Fetal Liver Kinase-2,Fetal Liver Kinase-3,Stem Cell Tyrosine Kinase 1,Antigen, CD135,Fetal Liver Kinase 2,Fetal Liver Kinase 3,fms Like Tyrosine Kinase 3

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