Expanding landscape of kinase inhibitor research in 25 years (2001-2025) and advancements of next-generation kinase inhibitors.

Protein kinases regulate many aspects of cellular processes and control signaling pathways involved in growth, apoptosis, metabolism and immune responses. Dysfunction of kinase activities lead to alterations of cellular signaling pathways and cause cancers, metabolic disorders and autoimmune diseases. Hence kinases have become the most promising targeted enzymes for tackling several diseases and kinase inhibitors (KIs)have been developed. Since approval of imatinib, the first kinase inhibitor approved by the US FDA in 2001, the area of KIs drug discovery research has been flourished tremendously. In the past twenty-five years (2001-2025), the FDA approved 95 small molecule KIs to the global market (till September 2025) and other regulatory bodies approved more than 13 KIs for different indications. The KIs are well demonstrated as therapeutic agents not only for cancers, but also for autoimmune diseases and metabolic disorders. However, many cases of mutation related drug resistances become main concern for using prior-generation KIs. Next-generation (NextGen) KIs are required to tackle the diseases further. The developments of different KIs have appeared in a few previous articles in different time frames. In most cases, chemical synthesis methods, physicochemical properties and binding modes have been discussed in most of the review articles. Trends of developing NextGen KIs for different indications and updated collective summary including all the approved KIs till today are still rare or yet to be found. Here, we summarize the discovery strategies for all approved KIs to the markets. Our discussion includes mutation related issues, evolution of different generations of KIs and the development of NextGen KIs. In addition, inhibition of signaling pathways by the KIs, biological implications and future perspectives of NextGen KIs are also discussed.