Structural modifications at the 6-position of thieno[2,3-d]pyrimidines and their effects on potency at FLT3 for treatment of acute myeloid leukemia

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Title
Structural modifications at the 6-position of thieno[2,3-d]pyrimidines and their effects on potency at FLT3 for treatment of acute myeloid leukemia
Author(s)
H Kim; C Lee; J S Yang; S Choi; C H Park; Jong Soon Kang; Soo Jin Oh; Ji Eun Yun; M H Kim; G Han
Bibliographic Citation
European Journal of Medicinal Chemistry, vol. 120, no. 1, pp. 74-85
Publication Year
2016
Abstract
Fms-like tyrosine kinase 3 (FLT3) is a well-known and important target for the treatment of acute myeloid leukemia (AML). A series of thieno[2,3-d]pyrimidine derivatives from a modification at the 6-position were synthesized to identify effective FLT3 inhibitors. Although compounds 1 and 2 emerged as promising FLT3 inhibitors among the synthesized compounds, both compounds exhibited poor metabolic stability in human and rat liver microsomes. Hence, further optimization was required for the discovery of FLT3 inhibitors, with a focus on improving metabolic stability. Compound 16d, which had structural modifications of the methyl group at the 5-position and the 4-(2-methylaminoethoxy) phenyl group at the 6-position, exhibited good inhibitory activity against FLT3 and showed effective antiproliferative activity against four leukemia cell lines, including MV4-11. Moreover, compound 16d displayed enhanced metabolic stability. The results of this study indicated that 16d could be a promising compound for further optimization and development as a potent FLT3 inhibitor.
Keyword
3-d]pyrimidineAcute myeloid leukemia (AML)Fms-like tyrosine kinase 3 (FLT3)Metabolic stabilityThieno[2
ISSN
0223-5234
Publisher
Elsevier
DOI
http://dx.doi.org/10.1016/j.ejmech.2016.05.022
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of Bioinfrastructure > Laboratory Animal Resource Center > 1. Journal Articles
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