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.
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.
authors.affiliation: Department of Integrated OMICS for Biomedical Sciences (WCU Program), Yonsei University, Seoul 120-749, Republic of Korea; Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Hyuntae
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Integrated OMICS for Biomedical Sciences (WCU Program), Yonsei University, Seoul 120-749, Republic of Korea; Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Chulho
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Integrated OMICS for Biomedical Sciences (WCU Program), Yonsei University, Seoul 120-749, Republic of Korea; Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Jee Sun
authors.initials: JS
authors.lastname: Yang
authors.affiliation: Department of Integrated OMICS for Biomedical Sciences (WCU Program), Yonsei University, Seoul 120-749, Republic of Korea; Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Seonghwi
authors.initials: S
authors.lastname: Choi
authors.affiliation: Division of New Drug Development, R&D Center, Jeil Pharmaceutical Co., Ltd., Gyeonggi-Do 449-861, Republic of Korea.
authors.forename: Chun-Ho
authors.initials: CH
authors.lastname: Park
authors.affiliation: Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Chungbuk 363-883, Republic of Korea.
authors.forename: Jong Soon
authors.initials: JS
authors.lastname: Kang
authors.affiliation: Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Chungbuk 363-883, Republic of Korea.
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Oh
authors.affiliation: Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Chungbuk 363-883, Republic of Korea.
authors.forename: Jieun
authors.initials: J
authors.lastname: Yun
authors.affiliation: Korea Drug Development Fund, A502, U-space2, 670 Daewangpangyo-Ro, Bundang-Gu, Seongnam-si, Gyeonggi-Do 463-400, Republic of Korea.
authors.forename: Myung-Hwa
authors.initials: MH
authors.lastname: Kim
authors.affiliation: Department of Integrated OMICS for Biomedical Sciences (WCU Program), Yonsei University, Seoul 120-749, Republic of Korea; Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea. Electronic address: gyoonhee@yonsei.ac.kr.
authors.forename: Gyoonhee
authors.initials: G
authors.lastname: Han
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004355:Drug Stability; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; D051941:fms-Like Tyrosine Kinase 3
keywords: Acute myeloid leukemia (AML); Fms-like tyrosine kinase 3 (FLT3); Metabolic stability; Thieno[2,3-d]pyrimidine