Unveiling the Advances in Protein Kinase: From Concept to Clinic

Protein kinase inhibitors (PKIs) are medicinal substances that target enzymes essential to vital cellular functions by controlling kinase activity. PKIs are being considered as targeted therapeutics to disrupt carcinogenic pathways since dysregulated kinase signalling is a hallmark of cancer. According to their binding mechanisms, PKIs are structurally categorised as follows: Type I inhibitors bind ATP competitively, Type II inhibitors target inactive kinase conformations, Type III inhibitors act through allosteric modulation, Type IV inhibitors operate independently of ATP, and Type V inhibitors, also referred to as covalent inhibitors, create irreversible bonds with target residues. PKIs have shown promise as a treatment for a number of malignancies, including leukemia, melanoma, lung, breast, and kidney cancers. While HER2-targeted PKIs have greatly improved results in breast cancer, targeting EGFR and ALK mutations has enhanced the treatment of lung cancer. Treatments for melanoma target BRAF and MEK inhibitors, while those for renal cell carcinoma concentrate on VEGF and mTOR pathways. Tyrosine kinase inhibitors have made significant strides in treating chronic myeloid leukemia, improving remission rates. Notwithstanding these achievements, resistance mechanisms still pose a threat to the efficacy of treatment, highlighting the necessity of continued investigation into next-generation PKIs and combination approaches to improve clinical outcomes for a range of cancer types. This article provides a comprehensive review of recent advancements in PKI research, including their mechanisms, therapeutic applications, and strategies to overcome drug resistance.