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. 2022 Jun 2;13(7):840-849.
doi: 10.1039/d2md00105e. eCollection 2022 Jul 20.

Novel etodolac derivatives as eukaryotic elongation factor 2 kinase (eEF2K) inhibitors for targeted cancer therapy

Ferah Comert Onder  1   2   3 , Pinar Siyah  4 , Serdar Durdagi  4 , Mehmet Ay  3 , Bulent Ozpolat  2   5
Affiliations

Novel etodolac derivatives as eukaryotic elongation factor 2 kinase (eEF2K) inhibitors for targeted cancer therapy

Ferah Comert Onder et al. RSC Med Chem. .

Abstract

Eukaryotic elongation factor 2 kinase (eEF2K) has been shown to be an important molecular driver of tumorigenesis and validated as a potential novel molecular target in various solid cancers including triple negative breast cancer (TNBC). Therefore, there has been significant interest in identifying novel inhibitors of eEF2K for the development of targeted therapeutics and clinical translation. Herein, we investigated the effects of indole ring containing derivatives of etodolac, a nonsteroidal anti-inflammatory (NSAID) drug, as potential eEF2K inhibitors and we designed and synthesized seven novel compounds with a pyrano[3,4-b] indole core structure. We evaluated the eEF2K inhibitory activity of seven of these novel compounds using in silico molecular modeling and in vitro studies in TNBC cell lines. We identified two novel compounds (EC1 and EC7) with significant in vitro activity in inhibiting eEF2K in TNBC cells. In conclusion, our studies indicate that pyrano[3,4-b] indole scaffold containing compounds demonstrate marked eEF2K inhibitory activity and they may be used as eEF2K inhibitors for the development of eEF2K-targeted therapeutics.

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Conflict of interest statement

The authors declare that they have no known competing financial interests.

Figures

Fig. 1
Fig. 1. Some indole ring containing anticancer drugs.
Fig. 2
Fig. 2. Synthesis pathway of novel etodolac derivatives as eEF2K inhibitors. Reagents and conditions: (i) EDCI, HOBt, DIPEA, rt, 48 h for EC1–EC3; (ii) T3P, DCM, rt, 24 h for EC4–EC7.
Fig. 3
Fig. 3. Normal distributions of LigFitProt (left) and LigFitLig (right) RMSDs of the studied compounds.
Fig. 4
Fig. 4. 3D and 2D ligand interaction diagram of EC1 at the binding pocket of eEF2K.
Fig. 5
Fig. 5. 3D and 2D ligand interaction diagram of EC7 at the binding pocket of eEF2K.
Fig. 6
Fig. 6. Western blot analysis of the synthesized compounds in TNBC cells. MDA-MB-231 cells were treated with the compounds for 2 h in the range of 2.5–20 μM to determine the eEF2K inhibitory activity as indicated by reduction of its downstream target pEF2 (Thr56).
Fig. 7
Fig. 7. An overview of novel eEF2K inhibitors.
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