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.

Death‐associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes

“…Flavonoids are a large class of polyphenolic 15 carbons based natural products that gained a lot of interest in medicinal chemistry as anticancer agents . Many of them targeted protein kinases and acted as promising hit compounds for further development .…”

Identification of TRD‐35 as Potent and Selective DRAK2 Inhibitor

“…Compounds with benzofuran‐3(2 H )‐one core were found to have a strong binding affinity for DRAK2 from in vitro kinase assays and displayed a significant cellular activity that can protect islet β‐cells from apoptosis . A series of thieno[2,3‐ b ]pyridine derivatives have been shown to have strong DRAK2 binding activity while lacking DRAK1 selectivity . Recently, Jung et al .…”

Synthesis of 2‐Organylchalcogenopheno[2,3‐b]pyridines from Elemental Chalcogen and NaBH4/PEG‐400 as a Reducing System: Antioxidant and Antinociceptive Properties

“…[38][39][40][41][42] Still, chalcogenophenes when associated to another biological active heterocycle, such as pyridine, usually makes the new compound biologically more active. [43][44][45][46][47] Thus, the development of new and efficient methodologies for the synthesis of chalcogenophene-fused pyridine as promising drug candidates is crucial in contemporary organic synthesis. In this sense, many compounds based on thieno [2,3-b]pyridine scaffolds have been widely studied.…”