Repurposing of investigational cancer drugs: Early phase discovery of dengue virus NS2B/NS3 protease inhibitors

Abstract

Dengue fever is a neglected vector‐borne disease and is more prevalent in Asia. Currently, no specific treatment is available. Given the time and cost of de novo drug discovery and development, an alternative option of drug repurposing is becoming an effective tool. We screened a library of 1127 pharmacologically active, metabolically stable, and structurally diverse small anticancer molecules to identify inhibitors of the dengue virus (DENV) NS2B/NS3 protease. Enzyme kinetics and inhibition data revealed four B‐cell lymphoma 2 inhibitors, that is, ABT263, ABT737, AT101, and TW37, as potent inhibitors of DENV NS2B/NS3 protease, with IC50 values of 0.86, 1.15, 0.81, and 0.89 µM, respectively. Mode of inhibition experiments and computational docking analyses indicated that ABT263 and ABT737 are competitive inhibitors, whereas AT101 and TW37 are noncompetitive inhibitors of the protease. With further evaluation, the identified inhibitors of the DENV NS2B/NS3 protease have the potential to be developed into specific anti‐dengue therapeutics.

The endoplasmic reticulum (ER): a crucial cellular hub in flavivirus infection and potential target site for antiviral interventions

“…Furthermore, several recent anti-cancer molecules turned out to be potent inhibitors of the DENV NS2B/NS3 protease as well. More specifically, four B-cell lymphoma-2 inhibitors from a library of structurally diverse small anti-cancer molecules exhibited the highest potency against the DENV NS2B/NS3 protease 71 . The repurposed anti-cancer drugs sunitinib and erlotinib are discussed in the section on assembly and virion budding.…”

Facile synthesis of substituted 2-aroylbenzo[b]thiophen-3-ols to form novel triazole hybrids using click chemistry

“…We envision that the 2-aroylbenzo[b]thiophen-3-ol core could provide access to diverse benzo[b]thiophene analogs for discovering new SERMs/SERDs. To extend our efforts on the discovery of early-phase inhibitor leads for developing antiviral and anticancer drugs, [29][30][31][32] we herein report a simple, one-pot synthetic method for the preparation of substituted 2-aroyl-benzo[b]thiophen-3-ol derivatives (5a-s) by reacting 2-mercaptobenzoic acid (6) with substituted aryl bromomethyl ketones (8a-s) in the presence of triethylamine in DMF. To further extend the scope of a 2-aroyl-benzo[b]thiophen-3-ol substrate (5), we introduced an alkyne moiety at the 3hydroxy position, conducted a click reaction, and prepared novel benzothiophene-triazole hybrids.…”

Synthesis and Experimental Structure of a Multifunctional Catechol‐Azomethinebenzoic Acid, DFT/DMol3 Calculations, and Molecular Docking with Hsp90

“…Diaryl‐imines formed from 2‐hydroxybenzaldehyde and anilines provide a chelate N imine ^O phenolate binding and have been extensively studied [1,2,4,5,7–15] . including many examples of 2,3‐dihydroxybenzaldehyde derivatives [16–20] . When including additionally to the 2,3‐dihydroxybenzaldehyde, the 4‐aminobenzoic acid functionality, the total number of studies is far smaller [8,12,21–25] .…”