Abstract
Gastrointestinal stromal tumors (GISTs) are the most common Mesenchymal Neoplasm of the gastrointestinal tract. The tumorigenesis of GISTs has been associated with the gain-of-function mutation and abnormal activation of the stem cell factor receptor (c-KIT) and platelet-derived growth factor receptor alpha (PDGFRα) kinases. Hence, inhibitors that target c-KIT and PDGFRα could be a therapeutic option for the treatment of GISTs. The available approved c-KIT/PDGFRα inhibitors possessed low efficacy with off-target effects, which necessitated the development of potent inhibitors. We performed computational studies of 48 pyrazolopyridine derivatives that showed inhibitory activity against c-KIT and PDGFRα to study the structural properties important for inhibition of both the kinases. The derivative of phenylurea, which has high activities for both c-KIT (pIC50 = 8.6) and PDGFRα (pIC50 = 8.1), was used as the representative compound for the dataset. Molecular docking and molecular dynamics simulation (100 ns) of compound 14 was performed. Compound 14 showed the formation of hydrogen bonding with Cys673, Glu640, and Asp810 in c-KIT, and Cys677, Glu644, and Asp836 in PDGFRα. The results also suggested that Thr670/T674 substitution in c-KIT/PDGFRα induced conformational changes at the binding site of the receptors. Three-dimensional quantitative structure–activity relationship (3D-QSAR) models were developed based on the inhibitors. Contour map analysis showed that electropositive and bulky substituents at the para-position and the meta-position of the benzyl ring of compound 14 was favorable and may increase the inhibitory activity against both c-KIT and PDGFRα. Analysis of the results suggested that having bulky and hydrophobic substituents that extend into the hydrophobic pocket of the binding site increases the activity for both c-KIT and PDGFRα. Based on the contour map analysis, 50 compounds were designed, and the activities were predicted. An evaluation of binding free energy showed that eight of the designed compounds have potential binding affinity with c-KIT/PDGFRα. Absorption, distribution, metabolism, excretion and toxicity (ADMET) and synthetic feasibility tests showed that the designed compounds have reasonable pharmaceutical properties and synthetic feasibility. Further experimental study of the designed compounds is recommended. The structural information from this study could provide useful insight into the future development of c-KIT and PDGFRα inhibitors.
Highlights
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract that arise from interstitial cells of Cajal (ICC) or from stem cells that differentiate toward ICCs [1,2]
A comparative study of compound 14 and compound 31 showed that compound 14 was able to form additional interactions at the hydrophobic pocket formed by residues from the catalytic loop and the αC-helix
The results suggested that possessing substituents that extended into the hydrophobic pocket could be crucial to increase the activity against c-KIT and PDGFRα
Summary
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract that arise from interstitial cells of Cajal (ICC) or from stem cells that differentiate toward ICCs [1,2]. Stem cell factor receptor (c-KIT) [5] and platelet-derived growth factor receptor alpha (PDGFRα) [6] kinases are members of Type 3 transmembrane receptor protein–tyrosine kinase (RPTK) family and play important roles in various cellular signaling processes. The binding of the stem cell factor to c-KIT leads to the dimerization of the kinase domains and the phosphorylation of specific tyrosine residues in the juxtamembrane regions, which in turn activates downstream signaling cascades that mediate cell survival, proliferation, and differentiation [8,9]. The PDGFRα kinases are expressed on the surface of several cell types and bind to the platelet-derived growth factor. The binding of the platelet-derived growth factor leads to kinase domain dimerization and activation. As a result of the role of the c-KIT and PDGFRα in the development and progression of GISTs, these kinases are considered to be promising therapeutic targets for the treatment of GISTs
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