Discovery of thienopyrimidine-based FLT3 inhibitors from the structural modification of known IKKβ inhibitors

Chun Ho Park, Chulho Lee, Jee Sun Yang, Bo Young Joe, Kwangwoo Chun, Hyuntae Kim, Hye Yun Kim, Jong Soon Kang, Jangik I. Lee, Myung Hwa Kim, Gyoonhee Han

Research output: Contribution to journalArticle

14 Citations (Scopus)

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 1 μM. Overall, these compounds represent a promising family of inhibitors for future development of a treatment for AML.

Original languageEnglish
Pages (from-to)2655-2660
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume24
Issue number12
DOIs
Publication statusPublished - 2014 Jun 15

Fingerprint

Acute Myeloid Leukemia
Rheumatoid Arthritis
Nitric Oxide
Phosphotransferases
thienopyrimidine
Neoplasms
1-(2-(3-methoxyphenyl)ethyl)phenoxy-3-(dimethylamino)-2-propanol
SPC-839

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Park, Chun Ho ; Lee, Chulho ; Yang, Jee Sun ; Joe, Bo Young ; Chun, Kwangwoo ; Kim, Hyuntae ; Kim, Hye Yun ; Kang, Jong Soon ; Lee, Jangik I. ; Kim, Myung Hwa ; Han, Gyoonhee. / Discovery of thienopyrimidine-based FLT3 inhibitors from the structural modification of known IKKβ inhibitors. In: Bioorganic and Medicinal Chemistry Letters. 2014 ; Vol. 24, No. 12. pp. 2655-2660.
@article{5ac28b43fa3f4f4a8c61586673f55b55,
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 1 μM. Overall, these compounds represent a promising family of inhibitors for future development of a treatment for AML.",
author = "Park, {Chun Ho} and Chulho Lee and Yang, {Jee Sun} and Joe, {Bo Young} and Kwangwoo Chun and Hyuntae Kim and Kim, {Hye Yun} and Kang, {Jong Soon} and Lee, {Jangik I.} and Kim, {Myung Hwa} and Gyoonhee Han",
year = "2014",
month = "6",
day = "15",
doi = "10.1016/j.bmcl.2014.04.058",
language = "English",
volume = "24",
pages = "2655--2660",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "12",

}

Discovery of thienopyrimidine-based FLT3 inhibitors from the structural modification of known IKKβ inhibitors. / Park, Chun Ho; Lee, Chulho; Yang, Jee Sun; Joe, Bo Young; Chun, Kwangwoo; Kim, Hyuntae; Kim, Hye Yun; Kang, Jong Soon; Lee, Jangik I.; Kim, Myung Hwa; Han, Gyoonhee.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 24, No. 12, 15.06.2014, p. 2655-2660.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Discovery of thienopyrimidine-based FLT3 inhibitors from the structural modification of known IKKβ inhibitors

AU - Park, Chun Ho

AU - Lee, Chulho

AU - Yang, Jee Sun

AU - Joe, Bo Young

AU - Chun, Kwangwoo

AU - Kim, Hyuntae

AU - Kim, Hye Yun

AU - Kang, Jong Soon

AU - Lee, Jangik I.

AU - Kim, Myung Hwa

AU - Han, Gyoonhee

PY - 2014/6/15

Y1 - 2014/6/15

N2 - 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 1 μM. Overall, these compounds represent a promising family of inhibitors for future development of a treatment for AML.

AB - 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 1 μM. Overall, these compounds represent a promising family of inhibitors for future development of a treatment for AML.

UR - http://www.scopus.com/inward/record.url?scp=84900800906&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84900800906&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2014.04.058

DO - 10.1016/j.bmcl.2014.04.058

M3 - Article

C2 - 24813730

AN - SCOPUS:84900800906

VL - 24

SP - 2655

EP - 2660

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 12

ER -