Cyclopropyl as a versatile tool in the development of kinase-targeted therapeutics.

The recognition of dysregulated kinase activity as a crucial factor in the etiology of multiple diseases has driven concerted efforts in drug discovery over the past four decades. Consequently, protein kinases have emerged as some of the most significant drug targets in the 21st century. Cyclopropane, the smallest cycloalkane in chemistry, has attracted significant interest from medicinal chemists, particularly in the development of kinase inhibitors. Its distinct properties offer advantages in modulating potency, selectivity, and pharmacokinetic profiles when incorporated into kinase inhibitor scaffolds. This significance is evidenced by the emergence of new-generation kinase inhibitors featuring cyclopropane, exemplified by the FDA-approved (2022) TYK2 inhibitor deucravacitinib, alongside several other candidates advancing through clinical trials. Here, we provide an overview of research concerning the important role of cyclopropane in the design and development of kinase inhibitors. We highlight its multifaceted roles in optimizing drug-target interactions and explore the rationale behind its inclusion in successful inhibitors. This review aims to inspire the development of novel bioactive cyclopropane-containing kinase inhibitors (including understudied kinases) to address a wide range of human diseases.