Title: Discovery of Dual Death-Associated Protein Related Apoptosis Inducing Protein Kinase 1 and 2 Inhibitors by a Scaffold Hopping Approach
Authors: Gao, Ling-Jie
Kovackova, Sona
Sala, Michal
Ramadori, Anna Teresa
De Jonghe, Steven
Herdewijn, Piet # ×
Issue Date: 2014
Series Title: JOURNAL OF MEDICINAL CHEMISTRY vol:57 issue:18 pages:7624-7643
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 a
ffinity (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.
ISSN: 0022-2623
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Medicinal Chemistry (Rega Institute)
× corresponding author
# (joint) last author

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