title: Synthesis and structure-activity relationship studies of 2-(1,3,4-oxadiazole-2(3H)-thione)-3-amino-5-arylthieno[2,3-b]pyridines as inhibitors of DRAK2.
abstract: In recent years, DAPK-related apoptosis-inducing protein kinase 2 (DRAK2) has emerged as a promising target for the treatment of a variety of autoimmune diseases and for the prevention of graft rejection after organ transplantation. However, medicinal chemistry optimization campaigns for the discovery of novel small-molecule inhibitors of DRAK2 have not yet been published. Screening of a proprietary compound library led to the discovery of a benzothiophene analogue that displays an affinity constant (Kd) value of 0.25 μM. Variation of the core scaffold and of the substitution pattern afforded a series of 5-arylthieno[2,3-b]pyridines with strong binding affinity (Kd = 0.008 μM for the most potent representative). These compounds also show promising activity in a functional biochemical DRAK2 enzyme assay, with an IC50 value of 0.029 μM for the most potent congener. Selectivity profiling of the most potent compounds revealed that they lack selectivity within the DAPK family of kinases. However, one of the less potent analogues is a selective ligand for DRAK2 and can be used as starting point for the synthesis of selective and potent DRAK2 inhibitors.
authors.affiliation: KU Leuven, Rega Institute for Medical Research, Laboratory of Medicinal Chemistry, Minderbroedersstraat 10, 3000 Leuven (Belgium); KU Leuven, Interface Valorisation Platform, Kapucijnenvoer 33, 3000 Leuven (Belgium).
authors.forename: Piotr
authors.initials: P
authors.lastname: Leonczak
authors.forename: Ling-Jie
authors.initials: LJ
authors.lastname: Gao
authors.forename: Anna Teresa
authors.initials: AT
authors.lastname: Ramadori
authors.forename: Eveline
authors.initials: E
authors.lastname: Lescrinier
authors.forename: Jef
authors.initials: J
authors.lastname: Rozenski
authors.forename: Steven
authors.initials: S
authors.lastname: De Jonghe
authors.forename: Piet
authors.initials: P
authors.lastname: Herdewijn
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D010069:Oxadiazoles / Q000737:chemistry*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D051017:Apoptosis Regulatory Proteins; D010069:Oxadiazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C583463:1,3,4-oxadiazole; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; C115489:STK17B protein, human
keywords: 1,3,4-oxadiazoles; DRAK2; heterocycles; medicinal chemistry