Identification of 2-Aminopyrimidine Derivatives as FLT3 Kinase Inhibitors with High Selectivity over c-KIT.

Abstract

Herein, we report two promising compounds 30 and 36 possessing nanomolar FLT3 inhibitory activities (IC50 = 1.5-7.2 nM), high selectivity over c-KIT (>1000-fold), and excellent anti-AML activity (MV4-11 IC50 = 0.8-3.2 nM). Furthermore, these two compounds efficiently inhibited the growth of multiple mutant BaF3 cells expressing FLT3-ITD, FLT3-D835V/F, FLT3-F691L, FLT3-ITD-F691L, and FLT3-ITD-D835Y. Oral administration of 30 and 36 at 6 mg/kg/d could significantly suppress tumor growth in the MV4-11 cell-inoculated xenograft model, exhibiting tumor growth inhibitory rates of 83.5% and 95.1%, respectively. Importantly, 36 could prolong the mouse survival time in the FLT3-ITD-TKD dual mutation syngeneic mouse model (BaF3-FLT3-ITD-D835Y) at a dose of 6 mg/kg p.o. bid/4W. No clear myelosuppression was observed in the treated group of 36 in the MPO strain of zebrafish, even at 10 μM. In summary, our data demonstrated that 36 may represent a promising candidate for the treatment of FLT3 mutant AML.

• Authors: Lexian Tong, Peipei Wang, Xuemei Li, Xiaowu Dong, Xiaobei Hu, Chang Wang, Tao Liu, Jia Li, Yubo Zhou
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 65 Issue 4 Pg. 3229-3248 (02 24 2022) ISSN: 1520-4804 [Electronic] United States
• PMID: 35138851 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• Pyrimidines
• 2-aminopyrimidine
• Flt3 protein, mouse
• KIT protein, human
• Proto-Oncogene Proteins c-kit
• fms-Like Tyrosine Kinase 3

Topics

• Animals
• Cell Line, Tumor
• Demyelinating Diseases (chemically induced, pathology)
• Dose-Response Relationship, Drug
• Humans
• Leukemia, Myeloid, Acute (drug therapy)
• Mice
• Mice, Inbred BALB C
• Protein Kinase Inhibitors (chemical synthesis, pharmacology, toxicity)
• Proto-Oncogene Proteins c-kit (antagonists & inhibitors)
• Pyrimidines (chemical synthesis, pharmacology, toxicity)
• Signal Transduction (drug effects)
• Substrate Specificity
• Xenograft Model Antitumor Assays
• Zebrafish
• fms-Like Tyrosine Kinase 3 (antagonists & inhibitors)