Therapeutic Targeting of Interleukin-2-Inducible T-Cell Kinase (ITK) for Cancer and Immunological Disorders: Potential Next-Generation ITK Inhibitors.

Interleukin-2-inducible T-cell kinase (ITK) is a critical tyrosine kinase enzyme that is involved in the activation and differentiation of T cells. ITK is mainly found in T cells, which plays an essential role in controlling T-cell receptor signaling and downstream pathways. ITK regulates the synthesis of cytokines, particularly interleukin-2 (IL-2), and the development of Th2 cells. ITK is of interest for drug discovery and molecular targeting in immunology, autoimmune diseases, and cancer. Here, we report a structure-based virtual screening utilizing a collection of small molecules obtained from the PubChem database with an eye on the discovery of drugs targeting ITK. The compounds were selected according to compliance with the Lipinski's rule of five. The molecular docking investigation focused on prioritizing binding affinity and specific interaction toward the kinase domain. The highest-ranking search results were subjected to identification of possible pan-assay interference compounds (PAINS), assessment of pharmacokinetic properties, and estimation of pharmacological activity using Prediction of Activity Spectra of Substances (PASS) analysis. The interactions among these chemicals and the salient residues in the interleukin-2-inducible T-cell kinase (ITK) kinase domain were unpacked using a two-dimensional approach. The reference inhibitor ITK-Inhibitor-2 (IMM) and four elucidated compounds with PubChem CIDs, namely, 90442621 (PFB), 141764004 (FTP), 149213796 (FPP), and 145983307 (MBD), showed significant binding affinity of -8, -10.4, -9.8, -10.2, and -10.7 kcal/mol, respectively, and high selectivity for the ITK binding pocket. In conclusion, this study reports on the potential of several compounds for therapeutic targeting of ITK. Furthermore, structural analysis revealed the interaction of proposed compounds and active site residues within the ATP-binding pocket is highly similar to known inhibitors but shares distinct interaction patterns that could improve specificity. This specificity and optimization hold potential for the development of next-generation ITK inhibitors with possible applications in the treatment of immune-related disorders and cancers. Further in vitro, in vivo, and translational clinical research are called for.