title: Synthesis and biological evaluation of novel thieno[2,3-d]pyrimidine-based FLT3 inhibitors as anti-leukemic agents.
abstract: The most common mutations in acute myeloid leukemia (AML) are those that cause the activation of FMS-like tyrosine kinase 3 (FLT3). Therefore, FLT3 is regarded as a potential target for the treatment of AML. A novel series of thieno[2,3-d]pyrimidine-based analogs was designed and synthesized as FLT3 inhibitors. All synthesized compounds were assayed for the tyrosine kinase activity of FLT3 and growth inhibitory activity in four human leukemia cell lines (THP1, MV4-11, K562, and HL-60). Among these compounds, compound 17a, which possesses relatively short and simple substituents at the C6 position of thieno[2,3-d]pyrimidine, emerged as the most promising anti-leukemic agent. Compound 17a exhibited potent inhibition of FLT3-positive leukemic cell growth and of the FLT3 D835Y kinase; such inhibition is required for the successful treatment of AML. The data supports the further investigation of this class of compounds as potential anti-leukemic agents.
authors.affiliation: 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: Graduate Program in Biomaterials Science & Engineering, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Chun-Ho
authors.initials: CH
authors.lastname: Park
authors.affiliation: 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: Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Hwan
authors.initials: H
authors.lastname: Kim
authors.affiliation: Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Changmok
authors.initials: C
authors.lastname: Oh
authors.affiliation: Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Yejoo
authors.initials: Y
authors.lastname: Choi
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: Jieun
authors.initials: J
authors.lastname: Yun
authors.affiliation: College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Yeonsu-gu, Incheon 406-840, Republic of Korea.
authors.forename: Jin-Hyun
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Korea Drug Development Fund, 14th Fl, KT&G SeodaemunTower, 21-1, Migeun-dong, Seodaemun-gu, Seoul, Republic of Korea.
authors.forename: Myung-Hwa
authors.initials: MH
authors.lastname: Kim
authors.affiliation: Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea; Department of Integrated OMICS for Biomedical Sciences (WCU Program), 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: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D005240:Feasibility Studies; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D051941:fms-Like Tyrosine Kinase 3; C030986:pyrimidine
keywords: Acute myeloid leukemia (AML); D835Y; FMS-like tyrosine kinase 3 (FLT3); Internal tandem duplications (ITD); Thieno[2,3-d]pyrimidine