NVP-TNKS656

A library of pyridine-based 1,2,4-triazolo-tethered indole conjugates were designed, synthesized, and evaluated for anti-proliferative activity against a panel of six human cancer cell lines. All the synthesized conjugates (14a-q) were found to be effective against the HT-29 cell line. Particularly conjugates 14a, 14n, and 14q exhibited promising cytotoxicity, with IC₅₀ values of 1 μM, 2.4 μM, and 3.6 μM, respectively, compared to the standard 5-fluorouracil (IC₅₀ = 5.31 μM). Cell cycle arrest at the G0/G1 phase was observed with these compounds, the mitochondrial membrane potential was interrupted, and the total ROS production was enhanced. Western blot and immunofluorescence experiments illustrated that these compounds inhibit the expression of markers that are involved in β-catenin and PI3K pathways. Molecular dynamics simulations demonstrated that compound 14a has major hydrophobic interactions and few H-bonding interactions with both PI3K and tankyrase proteins.

The signaling lymphocytic activation mol. F7 (CS-1) enables the selective killing of the myeloma cells with minimal side effects on the healthy tissue.In this study, we have modelled the 3D structure of CS-1 followed by performing mol. dynamic simulations.To develop a potential CS-1 modulator, a virtual screening of the 'Bioactive Compound Database'was conducted.The screening results have given three interacting regions.The best representative structure of each class and mode of action were revealed.Our study suggests compounds ICG-001, Avanafil, and BPTES, as novel drug candidates at the CS-1 protein target.The mol. dynamic simulation study reveals that the resulted compounds provide different binding patterns over the CS-1 Ig-like V-type domain in which Avanafil and BPTES provide stable interactions with their binding environment located at the bc-hi loops clefts and bc-fg loops clefts, resp.In contrast, compound ICG-001 shows more flexible and transient non-binding interaction due to the vast binding region over β-sheet strands consisting of H, C and D during the simulation timeline.We conclude that the identified compounds seem to be the best candidates to design a series of new compounds with the ability to bind to CS-1 with potential binding activity to its target.