Insight into Janus kinases specificity: From molecular architecture to cancer therapeutics

Janus Kinases (JAKs) play a crucial role as therapeutic targets for various cancers. However, the current JAK inhibitors (JAKi) available have limited therapeutic benefits due to their lack of selectivity. This review focuses on the structural analysis to elucidate the molecular determinants of JAKs specificity and the discovery and design of selective JAKi. It includes descriptions and comparison of different JAK structures and their binding sites, a comparative analysis of JAKi and their binding modes, detailed interaction fingerprints (IFPs), and an extensive structure-selectivity relationship (SSRs). Moreover, the review also explores the challenges and possibilities of using computational structure-based methods for discovering and designing selective JAKi. Other structure-based approaches, such as targeting the pseudokinase domain, as well as covalent and allosteric designs, are also covered. Based on this analysis, key determinants corresponding to JAK specificity and rational medicinal chemistry strategies are proposed to facilitate the development of highly selective JAKi. Overall, we aim to enhance the understanding of JAK specificity and explore strategies that can lead to the discovery of effective and selective JAKi in cancer therapy, thus improving the prognosis for cancer patients.