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

Hyuntae Kim, Chulho Lee, Jee Sun Yang, Seonghwi Choi, Chun Ho Park, Jong Soon Kang, Soo Jin Oh, Jieun Yun, Myung Hwa Kim, Gyoonhee Han

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)74-85
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume120
DOIs
Publication statusPublished - 2016 Sep 14

Fingerprint

fms-Like Tyrosine Kinase 3
Acute Myeloid Leukemia
Liver Microsomes
Liver
thieno(2,3-d)pyrimidine
Rats
Leukemia
Cells
Derivatives
Cell Line

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Kim, Hyuntae ; Lee, Chulho ; Yang, Jee Sun ; Choi, Seonghwi ; Park, Chun Ho ; Kang, Jong Soon ; Oh, Soo Jin ; Yun, Jieun ; Kim, Myung Hwa ; Han, Gyoonhee. / 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. In: European Journal of Medicinal Chemistry. 2016 ; Vol. 120. pp. 74-85.
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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.",
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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. / Kim, Hyuntae; Lee, Chulho; Yang, Jee Sun; Choi, Seonghwi; Park, Chun Ho; Kang, Jong Soon; Oh, Soo Jin; Yun, Jieun; Kim, Myung Hwa; Han, Gyoonhee.

In: European Journal of Medicinal Chemistry, Vol. 120, 14.09.2016, p. 74-85.

Research output: Contribution to journalArticle

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AU - Choi, Seonghwi

AU - Park, Chun Ho

AU - Kang, Jong Soon

AU - Oh, Soo Jin

AU - Yun, Jieun

AU - Kim, Myung Hwa

AU - Han, Gyoonhee

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