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

• Published in: European journal of medicinal chemistry Vol. 120; pp. 74 - 85
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 14.09.2016; Elsevier
• Subjects: Acute myeloid leukemia (AML); Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Drug Stability; Fms-like tyrosine kinase 3 (FLT3); fms-Like Tyrosine Kinase 3 - antagonists & inhibitors; Humans; Leukemia, Myeloid, Acute - drug therapy; Life Sciences & Biomedicine; Metabolic stability; Pharmacology & Pharmacy; Pyrimidines - chemistry; Pyrimidines - pharmacology; Rats; Science & Technology; Structure-Activity Relationship; Thieno[2,3-d]pyrimidine; Metabolic stability; Fms-like tyrosine kinase 3 (FLT3); Thieno[2,3-d]pyrimidine; Acute myeloid leukemia (AML); HEMATOPOIESIS; KINASE INHIBITOR; MUTATIONS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.05.022

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. [Display omitted] •Thieno[2,3-d]pyrimidine derivatives were synthesized and evaluated for FLT3 inhibition.•Thieno[2,3-d]pyrimidine derivative 16d effectively inhibited FLT3.•16d also showed antiproliferative activity against leukemia cells and enhanced metabolic stability.•16d is a promising compound for development as a FLT3 inhibitor.