Abstract
Tirbanibulin, an FDA-approved microtubule-targeting agent (MTA) introduced in 2020, represents a pioneering treatment for precancerous actinic keratosis. Despite its failure to gain approval as an anticancer agent due to insufficient efficacy, there remains potential value in extending its application into malignancy treatment through tirbanibulin-based derivatives. Tirbanibulin possesses a distinctive dual mechanism of action involving microtubule and Src inhibition, distinguishing it from other MTAs. In spite of its unique profile, exploration of tirbanibulin's structure-activity relationship (SAR) and the development of its derivatives are significantly limited in the current literature. This study addresses this gap by synthesizing various tirbanibulin derivatives and exploring their SAR through modifications in the core amide motif and the eastern benzylamine part. Our results underscore the critical role of the pyridinyl acetamide core structure for optimal cellular potency, with favorable tolerance observed for modifications at the para position of the benzylamine moiety. Particularly noteworthy is the analogue modified with p-fluorine benzylamine, which exhibited favorable in vivo PK profiles. These findings provide crucial insights into the potential advancement of tirbanibulin-based compounds as promising anticancer agents.