Discovery of indazoles as inhibitors of Tpl2 kinase

The Crystal Structure of Cancer Osaka Thyroid Kinase Reveals an Unexpected Kinase Domain Fold

“…The discovery of small molecule inhibitors in high throughput screens using COT kinase has been described (15)(16)(17)(18)(19)(20)(21)(22). Although some progress in the advancement of these molecules has been made, the low sequence homology of COT kinase to other serine-threonine (ST) kinases and the lack of structural information have hampered rapid progress in the understanding of the structure-activity relationship of the reported compounds.…”

“…Conservation of between groups of strongly similar and weakly similar properties are indicated with a colon or a period, respectively. tivity relationship of COT kinase inhibitors (15)(16)(17)(18)(19)(20)(21)(22)40) and reduces the predictability of structure-guided medicinal chemistry approaches, such as scaffold morphing and fragment growing. Although the presented co-crystal structures of COT kinase inhibitor complexes provided a first glimpse on the binding mode of early hits, the high throughput in vitro phosphorylation assay we report above became an invaluable tool to rapidly test newly synthesized derivatives for potency and selectivity.…”

“…Although the discovery of COT inhibitors has been reported in the literature (15)(16)(17)(18)(19)(20)(21)(22), difficulties in obtaining monodisperse protein and the lack of structural information have hampered the discovery of chemical compounds suitable for clinical studies. Careful selection of protein constructs and optimizations in the protein production procedures allowed us to obtain pure enzyme of exquisite biochemical activity.…”

Synthesis of indazole motifs and their medicinal importance: An overview

“…Through SAR modifications at the C3 and C5 positions of the indazole (39), we discovered compound with good potency in LANCE assay (0.047 µM) and cell-based pErk assay (0.079 µM) [116].…”

A Combination of Pharmacophore Modeling, Molecular Docking and Virtual Screening Study Reveals 3,5,7-Trihydroxy-2-(3,4,5-trihydroxyphenyl)- 4H-Chromen-4-One as a Potential Anti-Cancer Agent of COT Kinase

“…19 There are so many inhibitors have been identified to reduce the harmful effect of the COT kinase such as (E)-3-(2-amino-5 -( n a p h t h a l e n -2 -y l ) p y r i d i n -3 -y l ) a c r y l i c a c i d , 5-(5-(1H-indol-3-yl)-1H-pyrrolo [2,3-b]pyridin-3-yl)-1,3,4-oxadiazol-2-amine,5-(2-amino-5-(quinolin-3-yl)pyridin-3-yl)-1,3,4-oxadiazole-2(3H)-thione, 20 4-alkylamino-(1,7) naphthyridine-3-carbonitriles, 21 Indazoles, 22 1,7-naphthy ridine-3-carbonitriles, 23 thieno (2, 3-c) pyridine, 24,25 8-substituted-4-anilino-6-aminoquinoline-3-carbonitriles. 26 So there is a need to find out the small molecule cancer drugs.…”