Introduction to the themed collection on kinases

Medicinal chemistry targeting kinases has fundamentally shaped modern therapeutic strategies, especially in oncology and immunology. The journey began in the late 1990s with the advent of imatinib, the first small-molecule kinase inhibitor, which revolutionized treatment for chronic myeloid leukemia. This success catalyzed intensive drug discovery efforts, leading to the approval of many pivotal drugs for various types of cancer. Over the decades, medicinal chemists have navigated the challenge of developing selective inhibitors that balance efficacy with minimal off-target effects, expanding beyond tyrosine kinases to include serine/threonine and lipid kinases. These breakthroughs not only provided vital new treatment options but also established kinases as versatile and tractable drug targets. By the early 2020s, over 80 kinase inhibitors had reached the market, profoundly influencing therapeutic paradigms in oncology, autoimmune, and rare diseases.

The past decade has witnessed innovation in kinase-targeted therapies thanks to structural advances, allosteric modulation, and next-generation inhibitor design. Covalent inhibitors with greater precision, such as osimertinib, have achieved great success in advancing targeted therapy. Researchers are exploiting kinase degradation using protein degradation technologies like PROTACs or molecular glues. For kinases such as EGFR, PI3Kα and the JAK family, mutant selective targeting, as well as allosteric kinase inhibitors have been pursued for improved selectivity, addressing resistance and toxicity. Beyond oncology, novel kinase inhibitors are now explored for neurological and fibrotic diseases, broadening indications. Advances in structural biology, AI-driven drug design, and high-throughput screening have accelerated the discovery of inhibitors against challenging targets such as mutant BRAF, FGFR, and RET kinases. Recent approval of selective agents for rare cancers and inflammatory disorders underscore the expanding and maturing scope of kinase-focused medicinal chemistry.

Despite substantial progress, several challenges persist in kinase drug discovery. Drug resistance due to secondary mutations, pathway redundancy, and compensatory signaling limit long-term efficacy. Achieving ultra-high selectivity remains difficult given the conserved ATP-binding domains of kinases, raising the risk of off-target toxicity. Moreover, the therapeutic potential of kinases outside oncology is still relatively underexplored, in part due to complex biology and limited biomarkers. Future directions include harnessing structure-guided approaches, developing more allosteric and covalent inhibitors, and leveraging targeted protein degradation strategies to address resistance. Integrating multi-omics and systems biology will facilitate the identification of novel kinase dependencies and patient stratification.

This themed collection features some of the latest advances in medicinal chemistry effort around kinases, including evaluating understudied “dark” kinases, developing novel kinase degraders, allosteric inhibitors, pushing the limits of selectivity, as well as leveraging AI-assisted tools in design, drug-like property prediction and optimization. It is our hope that researchers in the field of small molecule drug discovery will enjoy reading these articles, and hope to inspire the next wave of novel discoveries.

Finally, as guest editors of this themed collection, we would like to thank all the authors for their contributions. In addition, we would like to thank the editorial staff on RSC Medicinal Chemistry for their guidance and support throughout the process.

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