Discovery of indirubin derivatives as new class of DRAK2 inhibitors from high throughput screening.
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.
Drug Discovery Division, Korea Research Institute of Chemical Technology, 141 Gajeong-Ro, Yuseong-gu, Daejeon 305-600, Republic of Korea.
Myoung Eun
ME
Jung
Drug Discovery Division, Korea Research Institute of Chemical Technology, 141 Gajeong-Ro, Yuseong-gu, Daejeon 305-600, Republic of Korea.
Byung Jin
BJ
Byun
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.
Hye-Mi
HM
Kim
Drug Discovery Division, Korea Research Institute of Chemical Technology, 141 Gajeong-Ro, Yuseong-gu, Daejeon 305-600, Republic of Korea.
Joo Yun
JY
Lee
School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea.
Jin-Hee
JH
Park
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.
Nari
N
Lee
Drug Discovery Division, Korea Research Institute of Chemical Technology, 141 Gajeong-Ro, Yuseong-gu, Daejeon 305-600, Republic of Korea.
You Hwa
YH
Son
Drug Discovery Division, Korea Research Institute of Chemical Technology, 141 Gajeong-Ro, Yuseong-gu, Daejeon 305-600, Republic of Korea.
Sang Un
SU
Choi
Department of Biomedical Science, CHA University of Medicine and Science, Kyunggi-do 463-400, Republic of Korea.
Kyung-Min
KM
Yang
Department of Biomedical Science, CHA University of Medicine and Science, Kyunggi-do 463-400, Republic of Korea.
Seong-Jin
SJ
Kim
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.
Kwangho
K
Lee
School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea. Electronic address: yongchul@gist.ac.kr.
Yong-Chul
YC
Kim
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.
Gildon
G
Choi
D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D051017:Apoptosis Regulatory Proteins; D007211:Indoles; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; C115489:STK17B protein, human; C027185:indirubin
DRAK1; DRAK2; Indirubin; Inhibitor; Kinase