615 Inverse docking assisted identification of flavonols as c-Kit, CDK2 and mTOR inhibitors for melanoma and non-melanoma skin cancer management

Abstract

Inflammatory skin diseases (ISDs) such as psoriasis and allergic contact dermatitis affects millions of people and poses a major public health burden. Aberrant cytokine production is a prominent characteristic of ISDs, although the molecular mechanisms underlying the imbalance between pro-and anti-inflammatory gene expression remain underexplored. Cterminal-binding protein (CtBP) 1 and 2 are transcriptional coregulators that repress diverse cellular processes. Our recently studies have uncovered a previously unrecognized proinflammatory role of CtBP in skin inflammation. CtBP1 overexpression in transgenic mouse keratinocytes causes a psoriasis-like phenotype including increased epidermal proliferation, immunocyte infiltration and proinflammatory cytokine expression in skin. Expression of the CtBPs is elevated in both human psoriatic skin lesions and the inflamed skin of two mouse ISD models, the imiquimod-induced psoriasis and the DNFB-induced contact hypersensitivity. Keratinocytes stimulated by imiquimod or DNFB exhibit transactivation of CtBP2 and CtBP-controlled proinflammatory genes that is accompanied by increased recruitment of CtBPs to the target promoters. Furthermore, we demonstrate that distinct CtBP-specific inhibitors can effectively suppress the expression of the CtBP target genes by evicting CtBPs from their target promoters and relieve symptoms of skin inflammation with topical treatment in both mouse ISD models. Together, these findings indicate that the CtBPs can promote skin inflammation by transactivating a select set of proinflammatory genes and suggest new avenues for therapeutic modulation of inflammation and immune responses in ISDs.

Identification of new fisetin analogs as kinase inhibitors: Data on synthesis and anti-skin cancer activities evaluation

“…Cell cultures were prepared, analyzed, and protein content was quantified using the BCA reagent assay (Thermo Fisher Scientific, Waltham, MA, USA). Protein electrophoresis: SDS-PAGE method (Protean 3 system, Bio-Rad, Hercules, CA, USA), followed by protein expression via the western blotting method, using the Bio-Rad analysis and imaging system as earlier described [1 , 2] . Analysis and graphs in the figures, including in vitro enzymatic kinase activities, western blot, scratch wound assays, and colony formation were plotted using GraphPad PRISM program suite, version 8 (GraphPad Software, Inc., La Jolla, CA, USA), and molecular docking analysis [ 1 , 2] .…”

“…Protein electrophoresis: SDS-PAGE method (Protean 3 system, Bio-Rad, Hercules, CA, USA), followed by protein expression via the western blotting method, using the Bio-Rad analysis and imaging system as earlier described [1 , 2] . Analysis and graphs in the figures, including in vitro enzymatic kinase activities, western blot, scratch wound assays, and colony formation were plotted using GraphPad PRISM program suite, version 8 (GraphPad Software, Inc., La Jolla, CA, USA), and molecular docking analysis [ 1 , 2] . In silico prediction of skin permeation, lipophilicity, absorption, distribution, metabolism, excretion (ADMET) properties of the analogs compared to the reference drug fisetin were performed and analyzed using the online SwissADME platform of the Swiss Institute of Bioinformatics [3] .…”

“…Densitometric data were collected, tallied and graphs were plotted to compare changes in the different treatment groups. The variations in protein and enzymes expressions in lysates and the differences in the proportion of colony sizes and numbers and wound closure areas were analyzed as in the associated research article [1] and as reported earlier [2] . Differences between samples treated with and without test compounds were measured and analyzed including protein and enzyme expression kinetics.…”

“…This dataset article provides supplementary data to the associated research article by Roy et al., [1] . Fig.…”

“… This article contains supplemental datasets of the recently published related research article “Synthesis, Inverse Docking-Assisted Identification and in vitro Biological Characterization of Flavonol-based Analogs of Fisetin as c-Kit, CDK2 and mTOR Inhibitors against Melanoma and Non-melanoma Skin Cancers” by Roy et al., [1] . It provides in-depth data not included in the original co-submission on the biophysical, molecular docking, and biological characterization of newly synthesized flavonol-based analogs of fisetin, a natural dietary small molecule with anticancer and anti-inflammatory properties.…”