title: Discovery of dual death-associated protein related apoptosis inducing protein kinase 1 and 2 inhibitors by a scaffold hopping approach.
abstract: DRAK2 emerged as a promising drug target for the treatment of autoimmune diseases and to prevent graft rejection after organ transplantation. Screening of a compound library in a DRAK2 binding assay led to the identification of an isothiazolo[5,4-b]pyridine derivative as a novel ligand for DRAK2, displaying a Kd value of 1.6 μM. Subsequent medicinal chemistry work led to the discovery of a thieno[2,3-b]pyridine derivative with strong DRAK2 binding affinity (Kd = 9 nM). Moreover, this compound also behaves as a functional inhibitor of DRAK2 enzymatic activity, displaying an IC50 value of 0.82 μM, although lacking selectivity, when tested against DRAK1. This paper describes for the first time functionally active dual DRAK1 and DRAK2 inhibitors that can be used as starting point for the synthesis of chemical tool compounds to study DRAK1 and DRAK2 biology, or they can be considered as hit compounds for hit-to-lead optimization campaigns in drug discovery programs.
authors.affiliation: Rega Institute for Medical Research, Laboratory of Medicinal Chemistry, KU Leuven , Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors.forename: Ling-Jie
authors.initials: LJ
authors.lastname: Gao
authors.forename: Sona
authors.initials: S
authors.lastname: Kovackova
authors.forename: Michal
authors.initials: M
authors.lastname: Sála
authors.forename: Anna Teresa
authors.initials: AT
authors.lastname: Ramadori
authors.forename: Steven
authors.initials: S
authors.lastname: De Jonghe
authors.forename: Piet
authors.initials: P
authors.lastname: Herdewijn
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors*; D055808:Drug Discovery; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D051017:Apoptosis Regulatory Proteins; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D017346:Protein Serine-Threonine Kinases; C115488:STK17A protein, human; C115489:STK17B protein, human