Abstract
The human Abl kinases comprise a family of proteins that are known to be key stimulus drivers in the signaling pathways modulating cell growth, cell survival, cell adhesion, and apoptosis. Recent collative studies have indicated the role of activation of Abl and Abl-related genes in solid tumors; further terming the Abl kinases as molecular switches which promote proliferation, tumorigenesis, and metastasis. The up-regulated Abl-kinase expression in colorectal cancer (CRC) and the role of Abl tyrosine kinase activity in the Matrigel invasion of CRC cells have cemented its significance in CRC advancement. Therefore, the requisite of identifying small molecules which serve as Abl selective inhibitors and designing anti-Abl therapies, particularly for CRC tumors, has driven this study. Curcumin has been touted as an effective inhibitor of cancer cells; however, it is limited by its physicochemical inadequacies. Hence, we have studied the behavior of heterocyclic derivatives of curcumin via computational tools such as pharmacophore-based virtual screening, molecular docking, free-energy binding, and ADME profiling. The most actively docked molecule, 3,5-bis(4-hydroxy-3-methylstyryl)-1H-pyrazole-1-carboxamide, was comparatively evaluated against Curcumin via molecular dynamics simulation using Desmond, Schrödinger. The study exhibited the improved stability of the derivative as compared to Curcumin in the tested protein pocket and displayed the interaction bonds with the contacted key amino acids. To further establish the claim, the derivatives were synthesized via the mechanism of cyclization of Curcumin and screened in vitro using SRB assay against human CRC cell line, HCT 116. The active derivative indicated an IC50 value of 5.85 µM, which was sevenfold lower as compared to Curcumin’s IC50 of 35.40 µM. Hence, the results base the potential role of the curcumin derivative in modulating Abl-kinase activity and in turn may have potential therapeutic value as a lead for CRC therapy.
Highlights
Cancer can be defined as genetic damage that leads to the faulty division of cells and mutation, and according to the Global Cancer Statistics of 2020, it is still one of the leading causes of mortality (Sung et al 2021)
The synthesis of the designed compounds was enabled via a simple one-pot condensation method in which Curcumin was treated with suitable substituted primary hydrazines and pyrimidine to obtain the studied pyrazole and isoxazole derivatives
The elaborated synthesis and characterization of these compounds have been reported in our previous study (Rodrigues et al 2021)
Summary
Cancer can be defined as genetic damage that leads to the faulty division of cells and mutation, and according to the Global Cancer Statistics of 2020, it is still one of the leading causes of mortality (Sung et al 2021). Studies correlating cancer and COVID-19 have suggested that patients with cancer have a threefold mortality vulnerability due to COVID-19 (Pathania et al 2021) (Dai et al 2020). To develop and target cancer therapy and chemotherapy, elaborate investigations have been carried out to identify the underlying molecular basis of cancer and one such driver in the cascade is the Abelson (Abl) tyrosine kinases family. Many studies have ubiquitously suggested that Abl tyrosine kinases play a regulatory role in controlling cell growth, survival, invasion, adhesion, and migration (Colicelli 2010)
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