Drug Discovery against Psoriasis: Identification of a New Potent FMS-like Tyrosine Kinase 3 (FLT3) Inhibitor, 1-(4-((1H-Pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea, That Showed Potent Activity in a Psoriatic Animal Model

Li, Guobo; Ma, Shuang; Yang, Lingling; Ji, Songbai; Fang, Zhen; Zhang, Guo; Wang, Lijiao; Zhong, Jiemin; Xiong, Yu; Wang, Jianghong; Huang, Shenzhen; Li, Linli; Xiang, Rong; Niu, Dawen; Chen, Ying‐Chun; Yang, Shengyong

doi:10.1021/acs.jmedchem.6b00604

Cited by 30 publications

(12 citation statements)

References 45 publications

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“…Among these, only CXCL8, CDH1, VEGFA, CCND1, CDK1 and CCNB1 have been reported in psoriasis vulgaris (53,54,(58)(59)(60)(61). In addition to these CCNA2, BUB1 and PLK1 have also been known in psoriasis (49,61,62). Furthermore, the present study, for the first time (to the best of our knowledge), reported CDC42 in psoriasis and its sub-type along with CCNA2, BUB1 and PLK1 in severe psoriasis vulgaris.…”

Section: Discussionsupporting

confidence: 51%

Transcriptomic landscaping of core genes and pathways of mild and severe psoriasis vulgaris

et al. 2020

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Psoriasis is a common chronic inflammatory skin disease affecting >125 million individuals worldwide. The therapeutic course for the disease is generally designed upon the severity of the disease. In the present study, the gene expression profile GSE78097, was retrieved from the National Centre of Biotechnology (NCBI)-Gene Expression Omnibus (GEO) database to explore the differentially expressed genes (DEGs) in mild and severe psoriasis using the Affy package in R software. The Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathways of the DEGs were analysed using clusterProfiler, Bioconductor, version 3.8. In addition, the STRING database was used to develop DEG-encoded proteins and a protein-protein interaction network (PPI). Cytoscape software, version 3.7.1 was utilized to construct a protein interaction association network and analyse the interaction of the candidate DEGs encoding proteins in psoriasis. The top 2 hub genes in Cytohubba plugin parameters were validated using immunohistochemical analysis in psoriasis tissues. A total of 382 and 3,001 dysregulated mild and severe psoriasis DEGs were reported, respectively. The dysregulated mild psoriasis genes were enriched in pathways involving cytokine-cytokine receptor interaction and rheumatoid arthritis, whereas cytokine-cytokine receptor interaction, cell cycle and cell adhesion molecules were the most enriched pathways in severe psoriasis group. PL1N1, TLR4, ADIPOQ, CXCL8, PDK4, CXCL1, CXCL5, LPL, AGT, LEP were hub genes in mild psoriasis, whereas BUB1, CCNB1, CCNA2, CDK1, CDH1, VEGFA, PLK1, CDC42, CCND1 and CXCL8 were reported hub genes in severe psoriasis. Among these, CDC42, for the first time (to the best of our knowledge), has been reported in the psoriasis transcriptome, with its involvement in the adaptive immune pathway. Furthermore, the immunoexpression of CDK1 and CDH1 proteins in psoriasis skin lesions were demonstrated using immunohistochemical analysis. On the whole, the findings of the present integrated bioinformatics and immunohistochemical study, may enhance our under-standing of the molecular events occurring in psoriasis, and these candidate genes and pathways together may prove to be therapeutic targets for psoriasis vulgaris.

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Section: Discussionsupporting

confidence: 51%

Transcriptomic landscaping of core genes and pathways of mild and severe psoriasis vulgaris

et al. 2020

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“…By using the KINOMEscan service in Eurofins DiscoverX to perform kinase profiling for 23 against a panel of kinases, we found that 23 manifested >90% inhibition at 10 μM for Flt3, DYRK1B, and GSK3β (Table S5). Previously, Flt3 has been linked to dendritic cell-mediated immune responses, which may be possibly involved in regulation of inflammatory factors in the PD model. Moreover, both DYRK1B and GSK3β have been identified as potential targets for PD and other neurodegenerative diseases. , These off-targets may not only help to interpret the efficacy of 23 in the MPTP-induced PD mouse models but also suggest new possible directions (e.g., multiple-targeting IDO/TDO and GSK3β) to develop agents for PD treatment.…”

Section: Resultsmentioning

confidence: 99%

X-ray Structure-Guided Discovery of a Potent, Orally Bioavailable, Dual Human Indoleamine/Tryptophan 2,3-Dioxygenase (hIDO/hTDO) Inhibitor That Shows Activity in a Mouse Model of Parkinson’s Disease

Ning

Huo

et al. 2021

J. Med. Chem.

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Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase (hTDO) have been closely linked to the pathogenesis of Parkinson's disease (PD); nevertheless, development of dual hIDO1 and hTDO inhibitors to evaluate their potential efficacy against PD is still lacking. Here, we report biochemical, biophysical, and computational analyses revealing that 1H-indazole-4-amines inhibit both hIDO1 and hTDO by a mechanism involving direct coordination with the heme ferrous and ferric states. Crystal structure-guided optimization led to 23, which manifested IC 50 values of 0.64 and 0.04 μM to hIDO1 and hTDO, respectively, and had good pharmacokinetic properties and brain penetration in mice. 23 showed efficacy against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse motor coordination deficits, comparable to Madopar, an anti-PD medicine. Further studies revealed that different from Madopar, 23 likely has specific anti-PD mechanisms involving lowering IDO1 expression, alleviating dopaminergic neurodegeneration, reducing inflammatory cytokines and quinolinic acid in mouse brain, and increasing kynurenic acid in mouse blood.

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“…For sorafenib, the well-known target vascular endothelial growth factor receptor 2 (VEGFR2) , was ranked at number 6 by IFPTarget (Table S3), and a total of 29 kinase entries were ranked within the top 1% of the retrieved database (Table S3). By comparing the predicted binding poses of sorafenib with the complex crystal structures of the top-ranked targets, we observed that sorafenib has a similar binding mode as structurally different inhibitors/ligands to targets including cytochrome BC1, acetylcholinesterase, and poly[ADP-ribose]polymerase 14 (PAP14) (Figure d–f).…”

Section: Results and Discussionmentioning

confidence: 99%

IFPTarget: A Customized Virtual Target Identification Method Based on Protein–Ligand Interaction Fingerprinting Analyses

Liu

et al. 2017

J. Chem. Inf. Model.

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Small-molecule target identification is an important and challenging task for chemical biology and drug discovery. Structure-based virtual target identification has been widely used, which infers and prioritizes potential protein targets for the molecule of interest (MOI) principally via a scoring function. However, current "universal" scoring functions may not always accurately identify targets to which the MOI binds from the retrieved target database, in part due to a lack of consideration of the important binding features for an individual target. Here, we present IFPTarget, a customized virtual target identification method, which uses an interaction fingerprinting (IFP) method for target-specific interaction analyses and a comprehensive index (Cvalue) for target ranking. Evaluation results indicate that the IFP method enables substantially improved binding pose prediction, and Cvalue has an excellent performance in target ranking for the test set. When applied to screen against our established target library that contains 11,863 protein structures covering 2842 unique targets, IFPTarget could retrieve known targets within the top-ranked list and identified new potential targets for chemically diverse drugs. IFPTarget prediction led to the identification of the metallo-β-lactamase VIM-2 as a target for quercetin as validated by enzymatic inhibition assays. This study provides a new in silico target identification tool and will aid future efforts to develop new target-customized methods for target identification.

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Drug Discovery against Psoriasis: Identification of a New Potent FMS-like Tyrosine Kinase 3 (FLT3) Inhibitor, 1-(4-((1H-Pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea, That Showed Potent Activity in a Psoriatic Animal Model

Cited by 30 publications

References 45 publications

Transcriptomic landscaping of core genes and pathways of mild and severe psoriasis vulgaris

Transcriptomic landscaping of core genes and pathways of mild and severe psoriasis vulgaris

X-ray Structure-Guided Discovery of a Potent, Orally Bioavailable, Dual Human Indoleamine/Tryptophan 2,3-Dioxygenase (hIDO/hTDO) Inhibitor That Shows Activity in a Mouse Model of Parkinson’s Disease

IFPTarget: A Customized Virtual Target Identification Method Based on Protein–Ligand Interaction Fingerprinting Analyses

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