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

  • Bioorg Med Chem Lett. 2016 Jun 1;26(11):2719-23. doi: 10.1016/j.bmcl.2016.03.111.
Myoung Eun Jung  1 ,  Byung Jin Byun  1 ,  Hye-Mi Kim  2 ,  Joo Yun Lee  1 ,  Jin-Hee Park  3 ,  Nari Lee  2 ,  You Hwa Son  1 ,  Sang Un Choi  1 ,  Kyung-Min Yang  4 ,  Seong-Jin Kim  4 ,  Kwangho Lee  2 ,  Yong-Chul Kim  5 ,  Gildon Choi  6
Affiliations
  • 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: [email protected].
  • 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: [email protected].
PMID: 27106709 DOI: 10.1016/j.bmcl.2016.03.111
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.
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