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Development of Human Protein Kinase ASK1 Inhibitors
Apoptosis signal-regulating kinase 1 (ASK1, also termed MAP3K5) is a mitogen-activated protein kinase (MAPK) that is involved in transduction of apoptotic signals under a variety of stress conditions. A series of studies have indicated that ASK1 plays important roles in many cardiovascular, neurodegenerative diseases and cancer suggesting that small-molecule compounds inhibiting ASK1 could possibly be used for the amelioration of the development of these pathologies.
OTAVAchemicals Ltd. has developed two novel classes of ASK1 using both in silico and in vitro approaches. The virtual screening experiments were carried out targeting the ATP binding site of ASK1 with the OTAVAchemicals’s in-stock compound collection. The most promising compounds have been selected and taken for the kinase assay study.



In vitro kinase assay revealed that derivatives of 3H-naphtho[1,2,3-de]quinoline-2,7-dione possess inhibitory activity towards ASK1. Compound ethyl 2,7-dioxo-2,7-dihydro-3H-naphtho[1,2,3-de]quinoline-1-carboxylate (NQDI-1) inhibited ASK1 with a Ki of 500 nM (Fig. 1). In our preliminary selectivity study this compound exhibited specific inhibitory activity towards ASK1 (Table 1). 


ASK1 inhoibitor NQDI-1


Fig.1. The chemical structure of inhibitor NQDI-1 and its binding mode in ASK1 active site.


Table 1. Residual Activity of Protein Kinases (%) in the Presence of NQDI-1 at 25 μM Concentration

12.5 79 100 62 44 84 100 78


It was reported that NQDI-1 has prevented ROS-mediated apoptosis in the NG108-15 neuronal cell line (Nomura et al., Neurosci Lett. 2013, 549, 63). Moreover, the administration of NQDI-1 to laboratory animals attenuated renal dysfunction and histological changes characteristic for renal ischemia/reperfusion injury (El Eter, Cardiovasc Hematol Agents Med Chem. 2013, 11, 179). Therefore, inhibitor NQDI-1 has strong pharmacological potential. 



  • Identification of 3H-naphtho[1,2,3-de]quinoline-2,7-diones as inhibitors of apoptosis signal-regulating kinase 1 (ASK1). Volynets GP, Chekanov MO, Synyugin AR, Golub AG, Kukharenko OP, Bdzhola VG, Yarmoluk SM. J Med Chem. 2011, 54(8):2680-2686.



A series of 5-(5-Phenyl-furan-2-ylmethylene)-2-thioxo-thiazolidin-4-one derivatives has been synthesized and evaluated in vitro toward human protein kinase ASK1. It was revealed that compound 2-{5-[5-(3,4-dichlorophenyl)-furan-2-ylmethylene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propanoic acid (PFTA-1) inhibited ASK1 with a Ki of 340 nM (Fig. 2).


ASK1 inhibitor PFTA1

Fig. 2. The chemical structure of inhibitor PFTA-1 and its binding mode with ASK1 active site.


Table 2. Residual Activity of Protein Kinases (%) in the Presence of PFTA-1 at 10 μM Concentration
ASK1 Aurora A HGFR FGFR1 Tie2 JNK3 CK2
3 14 65 88 29 46 34
The inhibitory profiles of PFTA-1 were investigated on a small panel of protein kinases. These studies have demonstrated that PFTA-1 is a selective inhibitor of ASK1. 
  • Rational design of apoptosis signal-regulating kinase 1 inhibitors: discovering novel structural scaffold. Volynets GP, Bdzhola VG, Golub AG, Synyugin AR, Chekanov MO, Kukharenko OP, Yarmoluk SM. Eur. J. Med. Chem. 2013, 61: 104-115.

ASK1 Pharmacophore Model Derived from Diverse Classes of Inhibitors

The three-dimensional pharmacophore model of ASK1 inhibitors has been developed with PharmaGist program (Fig. 3). The positions of pharmacophore features in the model correspond to conformations of highly active ASK1 inhibitors in which they interact with ATP-binding site of ASK1. 

ASK1 inhibitor PFTA1

Fig. 3. ASK1 inhibitors pharmacophore model

The generated pharmacophore model allows accurately predict active and inactive compounds and can be of great use for virtual screening aimed at discovering novel ASK1 inhibitors.