4-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)-5(3)-(6-methylpyridin-2-yl)imidazole and -pyrazole derivatives as potent and selective inhibitors of transforming growth factor-β type I receptor kinase.
A series of 4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5(3)-(6-methylpyridin-2-yl)imidazoles and -pyrazoles 14a-c, 15a-c, 16a, 16b, 19a-d, 21a, and 21b has been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. Among them, the pyrazole derivative 21b inhibited ALK5 phosphorylation with an IC50 value of 0.018 μM and showed 95% inhibition at 0.03 μM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct. The 21b showed a high selectivity index of 284 against p38α MAP kinase. The binding pose of 21b generated by docking analysis reveals that it fits well into the ATP binding cavity of ALK5 by forming several hydrogen bond interactions.
Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, 11-1 Daehyun-dong, Seodaemun-gu, Seoul 120-750, Republic of Korea.
Cheng Hua
CH
Jin
Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, 11-1 Daehyun-dong, Seodaemun-gu, Seoul 120-750, Republic of Korea.
Maddeboina
M
Krishnaiah
Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, 11-1 Daehyun-dong, Seodaemun-gu, Seoul 120-750, Republic of Korea.
Domalapally
D
Sreenu
Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, 11-1 Daehyun-dong, Seodaemun-gu, Seoul 120-750, Republic of Korea.
Vura Bala
VB
Subrahmanyam
School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Hyun-Ju
HJ
Park
School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
So-Jung
SJ
Park
Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, 11-1 Daehyun-dong, Seodaemun-gu, Seoul 120-750, Republic of Korea.
Yhun Yhong
YY
Sheen
Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, 11-1 Daehyun-dong, Seodaemun-gu, Seoul 120-750, Republic of Korea. Electronic address: dkkim@ewha.ac.kr.
Dae-Kee
DK
Kim
D001665:Binding Sites; D020134:Catalytic Domain; D002460:Cell Line; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D018125:Receptors, Transforming Growth Factor beta; C031280:pyrazole; C029899:imidazole; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human
ALK5 inhibitor; Cancer; Cell-based luciferase reporter assay; Docking; Fibrosis; Kinase assay; TGF-β