Kinases and their derived inhibitors from natural products.

Protein kinase dysregulation is a hallmark of many cancers, yet their tumorigenic mechanisms remain elusive despite 60 years of study. Since learning that their mechanism includes catalyzing phosphorylation of amino acids in protein substrates, researchers began devising their inhibition strategies. Initially, protein kinase inhibitors (PKIs) derived from natural products were employed despite high cytotoxicity risks. While synthetic PKIs proved less toxic, they face significant drug resistance challenges. This review examines the progress in understanding protein kinases' role in cancer, their classification and modes of action since their discovery. To illuminate the path towards less toxic yet highly effective kinase inhibitors, this study analyzes the synthesis and modification of all FDA-approved natural product derived kinase inhibitors (NPDKIs) as well as those that failed clinical trials. By providing insights into successful and unsuccessful approaches, this review also aims to advance medicinal chemistry strategies for developing more effective and safer PKIs, potentially improving cancer treatment outcomes.