Search

Death‐associated protein kinase‐related apoptosis‐inducing protein kinase 2 (DRAK2) has become a promising target for drug development. In search of novel and selective DRAK2 inhibitor motif, in vitro screen kinase assay was established performed using in‐house chemical libraries. After through hit triage procedure, N2‐(3,5‐dichlorophenyl)‐5‐fluoro‐N4‐methylpyrimidine‐2,4‐diamine (1) was selected as initial hit with structural novelty and drug‐likeness. During hit validation, structure–activity relationship of 1 was thoroughly disclosed and TRD‐93 was finally validated as hit for DRAK2 inhibition. TRD‐93 is small (mw = 290) but selectively potent to DRAK2 (IC50 = 0.16 μM) over other kinases including DAPK family kinases. Molecular binding model study of TRD‐93 to DRAK2 is also discussed. [ABSTRACT FROM AUTHOR]

Apoptosis signal‐regulating kinase 1 (ASK1) is a member of mitogen‐activated protein kinase kinase kinase (MAP3K) family that involves downstream phosphorylation of MAP kinases, c‐Jun N‐terminal kinases, and p38 MAP kinases. ASK1 inhibitors could possibly be beneficial for ameliorating the development and progression of diseases. Especially, ASK1 has been of interest as one of therapeutic targets for nonalcoholic fatty liver disease as the most common chronic liver diseases including simple steatosis and nonalcoholic steatohepatitis. In this manuscript, novel ASK1 inhibitor lead KTA‐29 which has an imidazo[1,2‐b]pyridazine core with novel C6‐bicycloheptaneimidazole is disclosed. With the novel imidazo[1,2‐b]pyridazine core, structure‐activity‐relationship study for ASK1 potency is described and KTA‐29 affinity toward ASK1 with molecular modeling study is explained. [ABSTRACT FROM AUTHOR]

DAP kinase-related apoptosis-inducing protein kinase 2 (DRAK2) is a member of the death-associated protein kinase (DAPK) family[1] and originally identified as a proapoptotic protein with the ability to induce apoptosis when overexpressed in various cell types.[2] However, the apoptosis-inducing ability of DRAK2 seems to be controversial and influenced by cellular factors within a specific cell types.[[3]] Recently, it has been suggested that DRAK2 is closely involved in tumorigenesis; DRAK2 expression was found to be highly elevated in multiple tumor types such as basal-like and HER2-enriched breast cancers. B Vertex-3 b is a pyrimidine C5-methylated analog of B UC-3 b .[9] When B UC-3 b was assessed to ATP-binding site of 359 diverse kinases at 10 micromolar concentration, it bound to 337 kinases including CDK2, CDK5, JNK3, and others. We believe the nitrile of the B UC-3 b has hydrogen-bonding interaction to DRAK2 Lys62 and plays a key role for its kinase promiscuous activities. [Extracted from the article]

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 (IC 50 = 0.003 μM). We also propose that compound 16 may bind to the ATP-binding site of the enzyme based on enzyme kinetics and molecular docking studies. [ABSTRACT FROM AUTHOR]