Discovery of Dual Death-Associated Protein Related Apoptosis Inducing Protein Kinase 1 and 2 Inhibitors by a Scaffold Hopping Approach

• DOI: 10.1021/jm5007929
• Publication Date: 2014-09-02T11:22:24Z
• Authors: Ling-Jie Gao; Sona Kovackova; Michal Šála; Anna Teresa Ramadori; Steven De Jonghe; Piet Herdewijn
• Keywords: Chemical library; IC50; Derivative (finance)

DRAK2 emerged as a promising drug target for the treatment of autoimmune diseases and to prevent graft rejection after organ transplantation. Screening compound library in binding assay led identification an isothiazolo[5,4-b]pyridine derivative novel ligand DRAK2, displaying Kd value 1.6 μM. Subsequent medicinal chemistry work discovery thieno[2,3-b]pyridine with strong affinity (Kd = 9 nM). Moreover, this also behaves functional inhibitor enzymatic activity, IC50 0.82 μM, although lacking selectivity, when tested against DRAK1. This paper describes first time functionally active dual DRAK1 inhibitors that can be used starting point synthesis chemical tool compounds study biology, or they considered hit hit-to-lead optimization campaigns programs.