title: Discovery of thienopyrimidine-based FLT3 inhibitors from the structural modification of known IKKβ inhibitors.
abstract: Inactivation of the NF-κB signaling pathway by inhibition of IKKβ is a well-known approach to treat inflammatory diseases such as rheumatoid arthritis and cancer. Thienopyrimidine-based analogues were designed through modification of the known IKKβ inhibitor, SPC-839, and then biologically evaluated. The resulting analogues had good inhibitory activity against both nitric oxide and TNF-α, which are well-known inflammatory responses generated by activated NF-κB. However, no inhibitory activity against IKKβ was observed with these compounds. The thienopyrimidine-based analogues were subsequently screened for a target kinase, and FLT3, which is a potential target for acute myeloid leukemia (AML), was identified. Thienopyrimidine-based FLT3 inhibitors showed good inhibition profiles against FLT3 under 1μM. Overall, these compounds represent a promising family of inhibitors for future development of a treatment for AML.
authors.affiliation: Graduate Program in Biomaterials Science & Engineering, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea; Division of New Drug Development, R&D Center, Jeil Pharmaceutical Co., Ltd 117-1, Keungok-Ri, Baekam-Myun, Cheoin-Gu, Yongin-City, Kyunggi-Do 449-861, 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, Seodaemun-gu, 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, Seodaemun-gu, Seoul 120-749, Republic of Korea.
authors.forename: Jee Sun
authors.initials: JS
authors.lastname: Yang
authors.affiliation: Division of New Drug Development, R&D Center, Jeil Pharmaceutical Co., Ltd 117-1, Keungok-Ri, Baekam-Myun, Cheoin-Gu, Yongin-City, Kyunggi-Do 449-861, Republic of Korea.
authors.forename: Bo-Young
authors.initials: BY
authors.lastname: Joe
authors.affiliation: Division of New Drug Development, R&D Center, Jeil Pharmaceutical Co., Ltd 117-1, Keungok-Ri, Baekam-Myun, Cheoin-Gu, Yongin-City, Kyunggi-Do 449-861, Republic of Korea.
authors.forename: Kwangwoo
authors.initials: K
authors.lastname: Chun
authors.affiliation: Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea; Department of Biomedical Sciences (WCU Program), Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea.
authors.forename: Hyuntae
authors.initials: H
authors.lastname: Kim
authors.affiliation: Center for Neuro-Medicine of Brain Science Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors.forename: Hye Yun
authors.initials: HY
authors.lastname: Kim
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: College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 406-840, Republic of Korea.
authors.forename: Jangik I
authors.initials: JI
authors.lastname: Lee
authors.affiliation: Division of New Drug Development, R&D Center, Jeil Pharmaceutical Co., Ltd 117-1, Keungok-Ri, Baekam-Myun, Cheoin-Gu, Yongin-City, Kyunggi-Do 449-861, Republic of Korea. Electronic address: mhkim@kddf.org.
authors.forename: Myung-Hwa
authors.initials: MH
authors.lastname: Kim
authors.affiliation: Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea; Department of Biomedical Sciences (WCU Program), Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea. Electronic address: gyoonhee@yonsei.ac.kr.
authors.forename: Gyoonhee
authors.initials: G
authors.lastname: Han
mesh_terms: D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008301:Maleimides / Q000737:chemistry; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000737:chemistry; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
chemical_list: D008301:Maleimides; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; C000597429:SPC-839; D054852:Small Molecule Libraries; C476003:thienopyrimidine; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D051550:I-kappa B Kinase
keywords: Acute myeloid leukemia (AML); Anti-inflammation; FLT3; IKKβ; Thienopyrimidine