Drugging non-canonical kinases in cancer therapeutics: Molecular targets, underlying mechanisms and small-molecule inhibitors

Non-canonical kinases (NCKs) are emerging as druggable targets in oncology, yet a comprehensive map linking their molecular mechanisms and targeting strategies to small-molecule modulators is lacking. Based on the hallmarks of cancer, we explain how NCKs buffer replication stress to preserve genome integrity, reprogram metabolic and stress pathways, coordinate angiogenesis and invasion, and support durable remodeling of the immune-tumor microenvironment. We review preclinical progress from hit identification to lead optimization, highlighting exploitable ATP-site and allosteric pockets, targeted protein degradation, and rational dual-node designs, all supported by structural insights and phenotypic discovery. Early clinical signals from mTOR, ATR, and DNA-PKcs inhibitors, along with late-preclinical programs targeting eEF2K, TBK1, FAM20C, TRPM7, and WNKs, reveal context-dependent NCK vulnerabilities. With further exploration of NCK functions and structures, additional targeted drugs are likely to be developed, potentially transforming non-canonical kinase biology into durable precision oncology. Non-canonical kinases may orchestrate genomic instability, proliferation, metabolism, invasion, angiogenesis, immortality, and cell-death escape; thereby leading to the context-dependent vulnerabilities and multiple therapeutic entry points across cancer hallmarks.