An updated patent review of anaplastic lymphoma kinase inhibitors (2018–2022)

Deyi Ma, Mengrao Guo, Xin Zhai

Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase in the insulin receptor superfamily, has emerged as a promising drug target for multiple cancers. Up to now, a total of seven ALK inhibitors have been approved for clinical cancer treatment. However, the issue of resistance to ALK inhibitors was subsequently reported, which led to the exploration of novel generations of ALK inhibitors recently. This paper provides a comprehensive review of the patent literature from 2018 to 2022 about structures, pharmacological data of small molecular ALK inhibitors, and their utilization as anticancer agents. In addition, several potential ALK inhibitors on the market or under clinical investigations are described in detail. To date, there are no ALK inhibitors that have been approved are completely free of resistance issues, which is a plight needing urgent solution. Development of new ALK inhibitors through structure modification, multi-targeted inhibitors, type-I1/2 and type-II binding modes as well as PROTAC and drug conjugates are proceeding. Over the last 5 years, lorlatinib, entrectinib and ensartinib were approved, and an increasing number of studies on ALK inhibitors, especially on macrocyclic compounds, had demonstrated their promising therapeutic potency. Herein, we will discuss the last five years results of novel ALK inhibitors published in patent literatures. It may contribute impactful lessons regarding the discovery and development of novel ALK inhibitors to overcome the resistance issue.