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Bioorg Med Chem Lett. 2016 Jun 1;26(11):2719-23. doi: 10.1016/j.bmcl.2016.03.111. Epub 2016 Apr 1.

Discovery of indirubin derivatives as new class of DRAK2 inhibitors from high throughput screening.

Author information

1
Drug Discovery Division, Korea Research Institute of Chemical Technology, 141 Gajeong-Ro, Yuseong-gu, Daejeon 305-600, Republic of Korea.
2
Drug Discovery Division, Korea Research Institute of Chemical Technology, 141 Gajeong-Ro, Yuseong-gu, Daejeon 305-600, Republic of Korea; Medicinal Chemistry and Pharmacology, Korea University of Science and Technology (UST), 217 Gajeong-Ro, Yuseong-gu, Daejeon 305-350, Republic of Korea.
3
School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea.
4
Department of Biomedical Science, CHA University of Medicine and Science, Kyunggi-do 463-400, Republic of Korea.
5
School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea. Electronic address: yongchul@gist.ac.kr.
6
Drug Discovery Division, Korea Research Institute of Chemical Technology, 141 Gajeong-Ro, Yuseong-gu, Daejeon 305-600, Republic of Korea; Medicinal Chemistry and Pharmacology, Korea University of Science and Technology (UST), 217 Gajeong-Ro, Yuseong-gu, Daejeon 305-350, Republic of Korea. Electronic address: gchoi@krict.re.kr.

Abstract

DRAK2 is a serine/threonine kinase belonging to the death-associated protein kinase (DAPK) family and has emerged as a promising drug target for the treatment of autoimmune diseases and cancers. To identify small molecule inhibitors for DRAK2, we performed a high throughput screening campaign using in-house chemical library and identified indirubin-3'-monoximes as novel class of DRAK2 inhibitors. Among the compounds tested, compound 16 exhibited the most potent inhibitory activity against DRAK2 (IC50=0.003μM). We also propose that compound 16 may bind to the ATP-binding site of the enzyme based on enzyme kinetics and molecular docking studies.

KEYWORDS:

DRAK1; DRAK2; Indirubin; Inhibitor; Kinase

PMID:
27106709
DOI:
10.1016/j.bmcl.2016.03.111
[Indexed for MEDLINE]

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