Proteomics-based identification of cancer-associated proteins in chronic lymphocytic leukaemia

Alsagaby, Suliman A.; Brewis, Ian Andrew; Vijayakumar, Rajendran; Alhumaydhi, Fahad A.; Alwashmi, Ameen S. S.; Alharbi, Naif Khalaf; Abdulmonem, Waleed Al; Premanathan, Mariappan; Pratt, Guy; Fegan, Christopher; Pepper, Chris; Brennan, Paul

doi:10.1016/j.ejbt.2021.04.006

Cited by 2 publications

(1 citation statement)

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“…In addition, chromosomal aberrations, such as deletions in 17p and 11q are characteristics of high-risk CLL 4 . Furthermore, increased protein expression of CD38, CD49d, ZAP-70 and CXCR4 is associated with an aggressive form of CLL 3 , 5 – 7 .…”

Section: Introductionmentioning

confidence: 99%

In silico investigations identified Butyl Xanalterate to competently target CK2α (CSNK2A1) for therapy of chronic lymphocytic leukemia

Alsagaby

Iqbal

Ahmad

et al. 2022

Sci Rep

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Chronic lymphocytic leukemia (CLL) is an incurable malignancy of B-cells. In this study, bioinformatics analyses were conducted to identify possible pathogenic roles of CK2α, which is a protein encoded by CSNK2A1, in the progression and aggressiveness of CLL. Furthermore, various computational tools were used to search for a competent inhibitor of CK2α from fungal metabolites that could be proposed for CLL therapy. In CLL patients, high-expression of CSNK2A1 was associated with early need for therapy (n = 130, p < 0.0001) and short overall survival (OS; n = 107, p = 0.005). Consistently, bioinformatics analyses showed CSNK2A1 to associate with/play roles in CLL proliferation and survival-dependent pathways. Furthermore, PPI network analysis identified interaction partners of CK2α (PPI enrichment p value = 1 × 10–16) that associated with early need for therapy (n = 130, p < 0.003) and have been known to heavily impact on the progression of CLL. These findings constructed a rational for targeting CK2α for CLL therapy. Consequently, computational analyses reported 35 fungal metabolites out of 5820 (filtered from 19,967 metabolites) to have lower binding energy (ΔG: − 10.9 to − 11.7 kcal/mol) and better binding affinity (Kd: 9.77 × 107 M−1 to 3.77 × 108 M−1) compared with the native ligand (ΔG: − 10.8, Kd: 8.3 × 107 M−−1). Furthermore, molecular dynamics simulation study established that Butyl Xanalterate-CK2α complex continuously remained stable throughout the simulation time (100 ns). Moreover, Butyl Xanalterate interacted with most of the catalytic residues, where complex was stabilized by more than 65% hydrogen bond interactions, and a significant hydrophobic interaction with residue Phe113. Here, high-expression of CSNK2A1 was implicated in the progression and poor prognosis of CLL, making it a potential therapeutic target in the disease. Butyl Xanalterate showed stable and strong interactions with CK2α, thus we propose it as a competitive inhibitor of CK2α for CLL therapy.

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