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

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11 Citations (Scopus)

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

Bibliographical note

Funding Information:
This research was supported by a grant from the Translational Research Center for Protein Function Control (Grant NRF-2009-0083522 ), the Ministry of Science, ICT and Future Planning (Grant NRF-2013M3A6A4072536 ), the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (Grant NRF-2013R1A1A2008165 and Grant NRF-2015R1A6A3A01020077 ), the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI14C1324 ), and the KRIBB Research Initiative Program.

Publisher Copyright:
© 2016 Elsevier Masson SAS.

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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